TWI464170B - 5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine derivatives, preparation thereof and therapeutic use thereof - Google Patents

5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine derivatives, preparation thereof and therapeutic use thereof Download PDF

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TWI464170B
TWI464170B TW100100686A TW100100686A TWI464170B TW I464170 B TWI464170 B TW I464170B TW 100100686 A TW100100686 A TW 100100686A TW 100100686 A TW100100686 A TW 100100686A TW I464170 B TWI464170 B TW I464170B
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amino
dihydropyrido
keto
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ethyl
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Philippe Beauverger
Guillaume Begis
Sandrine Biscarrat
Olivier Duclos
Gary Mccort
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Sanofi Aventis
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Description

5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶衍生物，其製備及其治療用途5-keto-5,8-dihydropyrido[2,3-d]pyrimidine derivative, preparation thereof and therapeutic use thereof

本發明係關於5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶衍生物、其製備及其治療用途。This invention relates to 5-keto-5,8-dihydropyrido[2,3-d]pyrimidine derivatives, their preparation and their therapeutic use.

鈣為例如在心臟及大腦層面上引起反應變化的細胞內信號傳導之關鍵要素。鈣亦在諸如細胞凋亡、細胞週期調控、基因表現、激素信號傳導及對氧化應力之細胞反應的各種細胞內過程中具有作為第二信使之重要作用。為了誘導此等生物反應，鈣使用普遍存在之細胞內受體鈣調蛋白(calmodulin)。鈣-鈣調蛋白複合體可隨後尤其結合至並活化「Ca2+ /鈣調蛋白依賴性蛋白激酶」(CaMK)，CaMK為絲胺酸/蘇胺酸蛋白激酶。Calcium is a key element of intracellular signaling, for example, causing a change in response at the heart and brain levels. Calcium also plays an important role as a second messenger in various intracellular processes such as apoptosis, cell cycle regulation, gene expression, hormonal signaling, and cellular responses to oxidative stress. To induce such biological responses, calcium uses the ubiquitous intracellular receptor calmodulin. The calcium-calmodulin complex can then specifically bind to and activate "Ca 2+ /calmodulin-dependent protein kinase" (CaMK), which is a serine/threonine protein kinase.

CaMKII為CaMK家族之一員，其四種已知的同功異型物(α、β、γ及δ)分佈於各種組織類型中。因此，CaMKIIα及CaMKIIβ主要侷限於腦及骨骼肌中，而CaMKIIγ及CaMKIIδ表現於包括心臟、肺及腎之許多組織及器官中。CaMKII is a member of the CaMK family and its four known isoforms (α, β, γ, and δ) are distributed among various tissue types. Therefore, CaMKIIα and CaMKIIβ are mainly restricted to brain and skeletal muscle, while CaMKIIγ and CaMKIIδ are expressed in many tissues and organs including heart, lung and kidney.

近來，CaMKII之4種同功異型物(α、β、γ及δ)與相對無選擇競爭性之ATP抑制劑一起結晶(Rellos等人，Plosbiology 2010,8,e1000426)。正如所料，四種結構極其相似，此係由於CaMKII之四種同功異型物的極高序列同源性(尤其關於ATP結合袋)。基於此等資料，可認為結合至δ同功異型物之ATP結合袋的抑制劑亦為α、β及γ同功異型物之抑制劑。Recently, four isoforms of CaMKII (α, β, γ, and δ) crystallize with relatively non-selectively competitive ATP inhibitors (Rellos et al, Plosbiology 2010, 8, e1000426). As expected, the four structures are extremely similar due to the extremely high sequence homology of the four isoforms of CaMKII (especially with respect to ATP binding pockets). Based on these data, it is believed that the inhibitors of the ATP-binding pockets bound to the delta isoforms are also inhibitors of alpha, beta and gamma isoforms.

證明CaMKII在心臟病變發展過程中的有害作用之許多跡象已在文獻中有報導：Many indications of the harmful effects of CaMKII in the development of heart disease have been reported in the literature:

-　CaMKIIδ之表現及活性的增加已在心肥大之實驗模型及男性心機能不全中證實(Hagemann等人，Mol. Cell. Biochem. 2001,220:69-76；Boknik等人，Cardiovasc. Res. 2001,51:717-728；Hempel等人，Basic Res. Cardiol. 2002;97增刊1:I96-101；Colomer等人，Mol. Endocrinol. 2003,17:183-192；Zhang等人，Circ. Res. 2003,92:912-919；Currie等人，FEBS Lett. 1999,459:244-248；Hoch等人，Circ. Res. 1999,84:713-721；Kirchhefer等人，Cardiovasc. Res. 1999,42:254-261)；- The increase in CaMKIIδ expression and activity has been demonstrated in experimental models of cardiac hypertrophy and in male cardiac insufficiency (Hagemann et al., Mol. Cell. Biochem. 2001, 220: 69-76; Boknik et al., Cardiovasc. Res. 2001, 51:717-728; Hempel et al, Basic Res. Cardiol. 2002; 97 Supplement 1: I96-101; Colomer et al, Mol. Endocrinol. 2003, 17: 183-192; Zhang et al, Circ. Res. 2003 , 92: 912-919; Currie et al, FEBS Lett. 1999, 459: 244-248; Hoch et al, Circ. Res. 1999, 84: 713-721; Kirchhefer et al, Cardiovasc. Res. 1999, 42: 254-261);

-　心肥大及心機能不全之發展已在過度表現CaMKIIδ於心臟中之轉殖基因小鼠中建立(Zhang等人，Circ. Res. 2003,92:912-919；Zhang等人，J. Biol. Chem. 2002,277:1261-1267；Maier等人，Circ. Res. 2003,92:904-911)；- Development of cardiac hypertrophy and cardiac insufficiency has been established in mice that overexpress CaMKIIδ in the heart of the transgenic mice (Zhang et al, Circ. Res. 2003, 92: 912-919; Zhang et al, J. Biol. Chem. 2002, 277: 1261-1267; Maier et al, Circ. Res. 2003, 92: 904-911);

-　藉由抑制CaMKII來防止小鼠患上心肌梗塞、心律不整、心肥大及心機能不全已藉助於小分子型CaMKII活化抑制劑(KN-93抑制劑)、CaMKII偽受質之肽抑制劑(AC3-1)或藉助於攜有CaMKIIδ基因缺失之小鼠來證明(Zhang等人，Nat. Med. 2005,11:379-380；Yang等人，Am. J. Physiol. Heart Circ. Physiol. 2006,291:H3065-H3075；Vila-Petroff等人，Cardiovasc. Res. 2007,73:689-98；Wu等人，Circulation 2002,106:1288-1293；Khoo等人，Circulation 2006,114:1352-1359；Backs等人，Proc. Natl Acad. Sci. 2009,106:2342-2347；Ling等人，J. Clin. Invest. 2009,119:1230-40)。此等跡象證實CaMKII抑制劑用於預防及/或治療心肌梗塞、心律不整、心肥大及心機能不全之潛在用途。- Preventing myocardial infarction, arrhythmia, cardiac hypertrophy and cardiac insufficiency in mice by inhibiting CaMKII by means of small-molecule CaMKII activation inhibitors (KN-93 inhibitors), CaMKII pseudo-peptide inhibitors ( AC3-1) or by means of a mouse bearing a CaMKIIδ gene deletion (Zhang et al, Nat. Med. 2005, 11: 379-380; Yang et al, Am. J. Physiol. Heart Circ. Physiol. 2006 , 291: H3065-H3075; Vila-Petroff et al, Cardiovasc. Res. 2007, 73: 689-98; Wu et al, Circulation 2002, 106: 1288-1293; Khoo et al, Circulation 2006, 114: 1352-1359 ; Backs et al, Proc. Natl Acad. Sci. 2009, 106: 2342-2347; Ling et al, J. Clin. Invest. 2009, 119: 1230-40). These indications demonstrate the potential use of CaMKII inhibitors for the prevention and/or treatment of myocardial infarction, arrhythmia, cardiac hypertrophy and cardiac insufficiency.

此外，已證明CaMKIIδ之消除導致在大鼠頸動脈套囊病變模型中新生內膜形成減少80%(House等人，Arterioscler. Thromb. Vasc. Biol. 2008,28:441-7)，此指示CaMKII抑制劑亦可能用於治療再狹窄。Furthermore, the elimination of CaMKIIδ has been shown to result in a 80% reduction in neointimal formation in a rat carotid cuff lesion model (House et al, Arterioscler. Thromb. Vasc. Biol. 2008, 28:441-7), which indicates CaMKII Inhibitors may also be used to treat restenosis.

再者，CaMKII會促成肝星狀細胞之增殖(Soliman等人，Cell Calcium 2009,45,284-292)以及心臟纖維母細胞之增殖及由此等細胞產生細胞外基質(Zhang等人，J. Cardiovasc. Pharmacol. 2010,55:96-105)。Furthermore, CaMKII contributes to the proliferation of hepatic stellate cells (Soliman et al., Cell Calcium 2009, 45, 284-292) and the proliferation of cardiac fibroblasts and the production of extracellular matrices by such cells (Zhang et al., J. Cardiovasc. Pharmacol. 2010, 55: 96-105).

此等跡象使得CaMKII成為治療包括肝纖維化、心臟纖維化、胰纖維化、腎纖維化、肺纖維化、皮膚纖維化、腸纖維化及眼部纖維化之纖維變性疾病中的新治療標靶。These signs make CaMKII a new therapeutic target for the treatment of fibrotic diseases including liver fibrosis, cardiac fibrosis, pancreatic fibrosis, renal fibrosis, pulmonary fibrosis, skin fibrosis, intestinal fibrosis and ocular fibrosis. .

近來亦提出CaMKII與由內質網應力誘發之內皮細胞的細胞凋亡或由6-羥基多巴胺誘發之神經元細胞的細胞凋亡有關，該兩種凋亡可分別為動脈粥樣硬化及帕金森氏症(Parkinson's disease)中的重要事件(Timmins等人，J. Clin. Invest. 2009,119: 2925-2941)。此外，在由內質網之系統性應力所誘發的小鼠急性腎機能不全模型中，在CaMKIIγKO小鼠之情況中觀察到管狀上皮細胞之細胞凋亡的減少及腎功能之保持(Timmins等人，J. Clin. Invest. 2009,119:2925-2941)，此表明CaMKII抑制劑有可能用於治療腎病變，尤其急性腎機能不全。Recently, CaMKII has also been proposed to be involved in apoptosis of endothelial cells induced by endoplasmic reticulum stress or apoptosis of neuronal cells induced by 6-hydroxydopamine, which may be atherosclerosis and Parkinson's, respectively. Important events in Parkinson's disease (Timmins et al, J. Clin. Invest. 2009, 119: 2925-2941). In addition, in the mouse acute renal insufficiency model induced by systemic stress of the endoplasmic reticulum, the decrease in apoptosis and the maintenance of renal function in tubular epithelial cells were observed in the case of CaMKIIγKO mice (Timmins et al. , J. Clin. Invest. 2009, 119: 2925-2941), which suggests that CaMKII inhibitors may be used to treat nephropathy, especially acute renal insufficiency.

此外，近來已報導CaMKII之「自主」活性之肽抑制劑(在此情況下為CN21)的神經保護性作用(Vest等人，J. Biol. Chem. 2010,285: 20675-20682)。此種類型之CaMKII抑制可為中風後之神經保護提供新型治療手段。Furthermore, the neuroprotective effect of the "autonomous" peptide inhibitor of CaMKII (in this case, CN21) has recently been reported (Vest et al., J. Biol. Chem. 2010, 285: 20675-20682). This type of CaMKII inhibition provides a novel treatment for neuroprotection after stroke.

此外，在鼠類炎症源性疼痛模型中，已顯示用三氟拉嗪(trifluoperazine)抑制CaMKII活性允許機械源性異常疼痛及熱源性痛覺過敏的劑量依賴性逆轉(Luo等人，J. Pharm. Exp. Ther. 2008 325: 267-275)。此等結果表明CaMKII抑制劑有可能用於治療慢性疼痛。Furthermore, in a murine inflammatory pain model, it has been shown that inhibition of CaMKII activity with trifluoperazine allows for a dose-dependent reversal of mechanically-derived allodynia and heat-induced hyperalgesia (Luo et al., J. Pharm. Exp. Ther. 2008 325: 267-275). These results indicate that CaMKII inhibitors may be used to treat chronic pain.

亦已報導CaMKII抑制劑(尤其SMP-114)能夠抑制HIF-1α之表現且顯著抑制巨噬細胞中之VEGF產生(Westra等人，BMC Musculoskeletal Disorders 2010,11:61-72)。在此情況下，對CaMKII之抑制活性可能部分地引起SMP-114之抗關節炎作用，且一般而言，可認為CaMKII抑制劑有可能用於治療類風濕性關節炎。It has also been reported that CaMKII inhibitors (especially SMP-114) are capable of inhibiting the expression of HIF-1α and significantly inhibiting VEGF production in macrophages (Westra et al., BMC Musculoskeletal Disorders 2010, 11: 61-72). In this case, the inhibitory activity against CaMKII may partially cause the anti-arthritic effect of SMP-114, and in general, it is considered that a CaMKII inhibitor may be used for the treatment of rheumatoid arthritis.

若干競爭性CaMKII抑制劑已在文獻中為人熟知，例如KN-93及肽AIP(Autocamtide-2-相關性抑制性肽)。亦已將異噁唑衍生物描述為CaMKII抑制劑(EP 1 815 867)且近年來，已揭示作為CaMKII之自主活性抑制劑的肽，諸如CN21(WO 2009/042 906)。Several competitive CaMKII inhibitors are well known in the literature, such as KN-93 and peptide AIP (Autocamtide-2-related inhibitory peptide). The isoxazole derivative has also been described as a CaMKII inhibitor (EP 1 815 867) and in recent years, peptides have been disclosed which are inhibitors of autonomous activity of CaMKII, such as CN21 (WO 2009/042 906).

其他芳基-吲哚基順丁烯二醯亞胺型競爭性抑制劑(Levy 等人，Bioorg. Med. Chem. Letters 2008,18:2390-2394、2395-2398及2399-2403)已在文獻中有描述。亦已知具有嘧啶單元之非競爭性抑制劑(Mavunkel等人，Bioorg. Med. Chem. Letters 2008,18:2404-2408)。Other aryl-mercaptobutyleneimine-type competitive inhibitors (Levy et al, Bioorg. Med. Chem. Letters 2008, 18: 2390-2394, 2395-2398, and 2399-2403) are already in the literature. Described in. Non-competitive inhibitors with pyrimidine units are also known (Mavunkel et al, Bioorg. Med. Chem. Letters 2008, 18: 2404-2408).

本發明之一目標為對應於式(I)之新穎化合物，其為CaMKII抑制劑，One object of the present invention is a novel compound corresponding to formula (I) which is a CaMKII inhibitor,

其中：　A表示CH或C(烷基)；　X 表示CH、C(烷基)或N；　R1 、R2 、R3 及R4 可相同或不同且彼此獨立地表示：‧　氫原子；‧　直鏈、分支鏈或環狀烷基，視情況經以下一或多個取代：○　鹵素原子；○　-OR9 ；○　-NR9 R'9 ；○　-CN；○　-C(O)OR9 ；○　-C(O)NR9 R9' ；○　-S(O)p R10 ；○　-S(O)2 NR9 R'9 ；其中R 9 、R ' 9 、R 10 及p 如下定義；‧　基團-S(O)p R10 ，其中p及R10 如下定義；‧　基團-OR10 ，其中R10 如下定義；‧　鹵素原子；‧　基團-N(R11 )C(O)R12 ，其中(i)　R 11 及R 12 彼此獨立地表示氫原子或視情況經一或多個選自鹵素原子、基團-OR9 及基團-NR9 R'9 之取代基取代的直鏈、分支鏈或環狀烷基，或(ii)　R 11 及R 12 與其所連接之原子一起形成雜環烷基，以便形成內醯胺；‧　基團-N(R14 )-CH2 -C(O)NR15 R9 ，其中R 14 及R 15 與其所連接之原子一起形成雜環烷基，以便形成哌嗪酮且其中R 9 如下定義；‧　基團-C(O)NR16 R17 ，其中R 16 及R 17 與其所連接之氮原子一起形成雜環烷基；‧　基團-T-U ，其中：■　T 表示：○　單鍵，○　直鏈或分支鏈伸烷基，○　基團-C(O)-，○　基團-S(O)p -，其中p如下定義，或○　基團-O-(CH2 )n -，其中n如下定義，且U表示包含一或多個選自N、O及S(O)p之雜原子的雜環，其中p如下定義，該雜環為飽和、不飽和或芳族的，視情況經1、2或若干個選自以下之取代基單取代或二取代或多取代：　基團-OR7 ，其中R7 如下定義，　鹵素原子，　基團-C(O)R7 ，其中R7 如下定義，　直鏈、分支鏈或環狀烷基，視情況經一或多個選自鹵素原子、基團-OR10 、基團-NR9 R'9 及基團-CN之取代基取代，其中R9 、R'9 及R10 如下定義；及　飽和、不飽和或芳族雜環，視情況經一或多個選自鹵素原子、基團-OR9 、基團-NR9 R'9 及烷基之取代基取代，該等烷基視情況經一或多個鹵素原子取代；應瞭解，當U 為包含至少一個氮原子之雜環烷基時，該取代基宜選自：　基團-C(O)R7 ，其中R7 如下定義；及　直鏈、分支鏈或環狀烷基，視情況經一或多個選自鹵素原子、基團-OR10 、基團-NR9 R'9 及基團-CN之取代基取代，其中R9 、R'9 及R10 如下定義；且該取代基宜由該氮原子所攜帶，或■　T表示：○　基團-C(O)-；○　基團-S(O)2 -；或○　基團-O-(C2-C3)伸烷基-；且U表示基團-NR9 R'9 ，其中R9 及R'9 如下定義；或■　T表示：○　基團-C(O)-；或○　基團-O-(C2-C3)伸烷基-；且U 表示基團-OR9 ，其中R9 如下定義；或■　T表示：○　直鏈或分支鏈伸烷基；或○　基團-O-(C2-C3)伸烷基-；且U 表示基團-NR8 R9 ，其中R9 及R8 如下定義；或者選自R1、R2、R3 及R4 之兩個相鄰基團與攜帶其之兩個碳連接並形成視情況經一或多個直鏈、分支鏈或環狀烷基取代之飽和、不飽和或芳族雜環，該等烷基視情況經一或多個選自鹵素原子、基團-OR10 及基團-NR9 R'9 之取代基取代，其中R9 、R'9 及R10 如下定義，該雜環與芳族環稠合， R 5 表示：‧　直鏈或分支鏈烷基，視情況經一或多個選自鹵素原子、基團-OR9 、基團-NR9 R'9 、基團-CN、基團-C(O)NR9 R9' 、基團-S(O)p R10 及視情況經基團-NR9 R'9 取代之環烷基的取代基取代，其中R9 、R'9 、R10 及p如下定義，‧　環烷基，視情況經基團-NR9 R'9 取代，其中R9 及R'9 如下定義，●　烷氧基-OR9 ，其中R9 如下定義，●　芳基，視情況經一或多個選自基團(C1-C3)烷基、鹵素原子及基團-O-(C1-C3)烷基之取代基取代，或●　基團-(CH2 )t -R13 ，其中R 13 及t 如下定義，　R 6 表示氫原子或直鏈、分支鏈或環狀烷基，且其中： R 7 表示氫原子或視情況經一或多個選自以下之取代基取代的直鏈、分支鏈或環狀烷基：鹵素原子、基團-OR9 及基團-NR9 R'9 ，其中R9 及R'9 如下定義；　R 8 表示雜芳基，宜為吡啶；　R 9 及R' 9 彼此獨立地表示氫原子或直鏈、分支鏈或環狀烷基；　R 10 表示氫原子或視情況經一或多個鹵素原子取代之直鏈、分支鏈或環狀烷基，　R 13 表示視情況經一或多個選自直鏈、分支鏈或環狀烷基之取代基取代的雜芳基或雜環烷基，應瞭解當該雜環烷基包含至少一個氮原子時，此原子可視情況攜帶該取代基，　t 表示1或2，　n 表示0、1、2或3，且　p 表示0、1或2，其呈酸、鹼或與酸或鹼形成之加成鹽形式，以及呈水合物或溶劑合物形式。among them: A represents CH or C (alkyl); X represents CH, C (alkyl) or N; R1 , R2 , R3 and R4 may be the same or different and independently of each other: ‧ a hydrogen atom; ‧ a linear, branched or cyclic alkyl group, optionally substituted by one or more of the following: ○ halogen atom; ○ -OR 9 ; ○ -NR 9 R'9; ○ -CN; ○ -C(O)OR 9 ; ○ -C(O)NR 9 R 9' ; ○ -S(O) p R 10 ; ○ -S(O 2 NR 9 R'9; wherein R 9 , R ' 9 , R 10 and p are as defined below; ‧ group -S(O) p R 10 , wherein p and R 10 are as defined below; ‧ group -OR 10 , Wherein R 10 is as defined below; ‧ a halogen atom; ‧ a group -N(R 11 )C(O)R 12 , wherein (i) R 11 and R 12 independently of each other represent a hydrogen atom or, as the case may be, one or more a straight chain, a branched chain or a cyclic alkyl group substituted with a substituent of a halogen atom, a group -OR 9 and a group -NR 9 R' 9 , or (ii) R 11 and R 12 are formed together with the atom to which they are attached a heterocycloalkyl group to form an indoleamine; ‧ a group -N(R 14 )-CH 2 -C(O)NR 15 R 9 , wherein R 14 and R 15 together with the atom to which they are attached form a heterocycloalkyl group to form a piperazinone and 9 as defined below wherein R; ‧ group -C (O) NR 16 R 17 , wherein R 17 and R 16, and they are attached Together with the nitrogen atom form a heterocyclic group; ‧ per group -TU, wherein: ■ T represents: ○ a single bond, ○ a straight-chain or branched alkylene group, ○ a group -C (O) -, ○ a group - S(O) p -, wherein p is as defined below, or ○ group -O-(CH 2 ) n -, wherein n is as defined below, and U represents one or more selected from N, O and S(O)p a hetero atom heterocyclic ring wherein p is as defined below, which is saturated, unsaturated or aromatic, optionally substituted or disubstituted or polysubstituted with 1, 2 or several substituents selected from the group consisting of: a group -OR 7 , wherein R 7 is as defined below, Halogen atom, a group -C(O)R 7 , wherein R 7 is as defined below, a straight chain, a branched chain or a cyclic alkyl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a group -OR 10 , a group -NR 9 R' 9 and a group -CN, wherein R 9 , R' 9 and R 10 are defined as follows; and a saturated, unsaturated or aromatic heterocyclic ring, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a group -OR 9 , a group -NR 9 R' 9 and an alkyl group, as appropriate Substituted by one or more halogen atoms; it is understood that when U is a heterocycloalkyl group containing at least one nitrogen atom, the substituent is preferably selected from: a group -C(O)R 7 , wherein R 7 is as defined below; a straight chain, a branched chain or a cyclic alkyl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a group -OR 10 , a group -NR 9 R' 9 and a group -CN, wherein R 9 And R' 9 and R 10 are as defined below; and the substituent is preferably carried by the nitrogen atom, or ■ T represents: ○ group -C(O)-; ○ group -S(O) 2 -; or ○ a group -O-(C2-C3)alkyl-; and U represents a group -NR 9 R' 9 wherein R 9 and R' 9 are as defined below; or ■ T represents: ○ group -C(O) -; or ○ group -O-(C2-C3)alkylene-; and U represents a group -OR 9 wherein R 9 is as defined below; or ■ T represents: ○ straight or branched alkyl; or o a group -O-(C2-C3)alkylene-; and U represents a group -NR 8 R 9 wherein R 9 and R 8 are as defined below; or two phases selected from R1, R2, R3 and R4 An ortho group is bonded to two carbons carrying it and forms a saturated, unsaturated or aromatic heterocyclic ring optionally substituted with one or more straight chain, branched chain or cyclic alkyl groups, such as Or a plurality of substituents selected from the group consisting of a halogen atom, a group -OR 10 and a group -NR 9 R' 9 wherein R 9 , R' 9 and R 10 are as defined below, the heterocyclic ring Condensed with an aromatic ring, R 5 represents: ‧ a straight or branched alkyl group, optionally selected from one or more selected from the group consisting of a halogen atom, a group -OR 9 , a group -NR 9 R' 9 , a group -CN, a group -C ( O) NR 9 R 9 ' , a group -S(O) p R 10 and optionally substituted by a substituent of a cycloalkyl group substituted with a group -NR 9 R' 9 wherein R 9 , R' 9 , R 10 And p are as defined below, ‧ cycloalkyl, optionally substituted by the group -NR 9 R' 9 wherein R 9 and R' 9 are as defined below, ● alkoxy-OR 9 , wherein R 9 is as defined below, ● aryl , optionally substituted by one or more substituents selected from the group consisting of a (C1-C3) alkyl group, a halogen atom and a group -O-(C1-C3)alkyl group, or a group -(CH 2 ) t -R 13 , where R 13 and t are as defined below, R 6 represents a hydrogen atom or a straight chain, a branched chain or a cyclic alkyl group, and wherein: R 7 represents a hydrogen atom or, as the case may be, a linear, branched or cyclic alkyl group substituted with one or more substituents selected from the group consisting of a halogen atom, a group -OR 9 and a group -NR 9 R' 9 , Wherein R 9 and R' 9 are as defined below; R 8 represents a heteroaryl group, preferably pyridine; R 9 and R' 9 independently of each other represent a hydrogen atom or a straight chain, a branched chain or a cyclic alkyl group; R 10 represents a hydrogen atom or a linear, branched or cyclic alkyl group substituted with one or more halogen atoms as appropriate, R 13 represents a heteroaryl or heterocycloalkyl group optionally substituted with one or more substituents selected from a linear, branched or cyclic alkyl group, and it is understood that when the heterocycloalkyl group contains at least one nitrogen atom This atom may carry the substituent as appropriate. t means 1 or 2, n represents 0, 1, 2 or 3, and P represents 0, 1 or 2 in the form of an acid, a base or an addition salt formed with an acid or a base, and in the form of a hydrate or a solvate.

式(I)化合物可包含一或多個不對稱碳原子。因此，其可以對映異構體或非對映異構體形式存在。此等對映異構體及非對映異構體以及其混合物(包括外消旋混合物)構成本發明之一部分。The compound of formula (I) may contain one or more asymmetric carbon atoms. Thus, it may exist in enantiomeric or diastereomeric forms. Such enantiomers and diastereomers, as well as mixtures thereof, including racemic mixtures, form part of the present invention.

式(I)化合物可以鹼或酸加成鹽形式存在。該等加成鹽構成本發明之一部分。The compound of formula (I) may exist in the form of a base or an acid addition salt. These addition salts form part of the invention.

此等鹽可用醫藥學上可接受之酸製備，但適用於例如純化或分離式(I)化合物之其他酸之鹽亦構成本發明之一部分。Such salts can be prepared with pharmaceutically acceptable acids, but salts of other acids suitable for use in, for example, purification or isolation of a compound of formula (I) also form part of the present invention.

式(I)化合物亦可呈水合物或溶劑合物形式，亦即呈與一或多個水分子或與溶劑締合或組合之形式。該等水合物及溶劑合物亦構成本發明之一部分。The compounds of formula (I) may also be in the form of a hydrate or solvate, i.e., in association with or in combination with one or more water molecules or with a solvent. These hydrates and solvates also form part of the invention.

在本發明中，除非在文中另外說明，否則以下定義適用：　鹵素原子： 氟、氯、溴或碘原子；　烷基： 直鏈或分支鏈飽和脂族基，其可包含1、2、3、4、5或6個碳原子(縮寫為-(C1-C6)烷基)。舉例而言，可提及以下基團：(i)作為基團-C1烷基，甲基，(ii)作為基團-C2烷基，乙基，(iii)作為基團-C3烷基，丙基或異丙基，(iv)作為基團-C4烷基，丁基、異丁基或第三丁基，(v)作為基團-C5烷基，戊基或異戊基；　伸烷基： 如上所定義之直鏈或分支鏈飽和二價烷基，其可包含1、2、3、4或5個碳原子(縮寫為-(C1-C5)伸烷基-)。可提及之實例包括亞甲基(或-CH2-)、伸乙基(或-CH2-CH2-)或伸丙基(-CH2-CH2-CH2-或-C(CH3)2 -)；　環烷基 ：可包含3、4、5或6個碳原子之環狀烷基，亦縮寫為-(C3-C6)環烷基且其中所有碳原子均包含於環中。可提及之實例包括環丙基、環丁基、環戊基及環己基；　烷氧基 ：基團-O-烷基，其中烷基如上所定義。可提及之實例包括基團-O-(C1-C5)烷基或-(C1-C5)烷氧基，特別是(i)作為基團-O-C1烷基，基團-O甲基，(ii)作為基團-O-C2烷基，基團-O乙基，(iii)作為基團-O-C3烷基，基團-O丙基或-O異丙基，(iv)作為基團-O-C4烷基，基團-O丁基、-O異丁基或-O第三丁基，(v)作為基團-O-C5烷基，基團-O戊基、-O異戊基或-O新戊基；　芳基 ：包含5至10個碳原子且宜包含5至6個碳原子的單環或雙環芳族基。可提及之芳基之實例包括苯基及萘基；　雜環基 ：包含一或多個選自O、N及S之雜原子的3員至10員單環或雙環基團。In the present invention, the following definitions apply unless otherwise stated herein: a halogen atom: a fluorine, chlorine, bromine or iodine atom; Alkyl: a linear or branched saturated aliphatic group which may contain 1, 2, 3, 4, 5 or 6 carbon atoms (abbreviated as -(C1-C6)alkyl). By way of example, the following may be mentioned: (i) as a group -C1 alkyl, methyl, (ii) as a group -C2 alkyl, ethyl, (iii) as a group -C3 alkyl, a propyl or isopropyl group, (iv) as a group -C4 alkyl, butyl, isobutyl or tert-butyl, (v) as a group -C5 alkyl, pentyl or isopentyl; Alkyl group: a straight or branched chain saturated divalent alkyl group as defined above which may contain 1, 2, 3, 4 or 5 carbon atoms (abbreviated as -(C1-C5)alkylene-). Examples which may be mentioned include methylene (or -CH2-), extended ethyl (or -CH2-CH2-) or propyl (-CH2-CH2-CH2- or -C(CH3) 2- ); Cycloalkyl : a cyclic alkyl group which may contain 3, 4, 5 or 6 carbon atoms, also abbreviated as -(C3-C6)cycloalkyl and in which all carbon atoms are contained in the ring. Examples which may be mentioned include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; Alkoxy : group -O-alkyl, wherein alkyl is as defined above. Examples which may be mentioned include the group -O-(C1-C5)alkyl or -(C1-C5)alkoxy, in particular (i) as a group -O-C1 alkyl, group -Omethyl , (ii) as a group -O-C2 alkyl, group -Oethyl, (iii) as a group -O-C3 alkyl, group -Opropyl or -O isopropyl, (iv) As a group -O-C4 alkyl, a group -O butyl, -O-isobutyl or -O tert-butyl, (v) as a group -O-C5 alkyl, group -O-pentyl, -O isopentyl or -O neopentyl; Aryl : a monocyclic or bicyclic aromatic group containing 5 to 10 carbon atoms and preferably 5 to 6 carbon atoms. Examples of aryl groups which may be mentioned include phenyl and naphthyl; Heterocyclyl : A 3- to 10-membered monocyclic or bicyclic group containing one or more heteroatoms selected from O, N and S.

該雜環可為飽和或部分不飽和的且可包含一或多個雙鍵。因而將其稱為雜環烷基 。可提及之非芳族或雜環烷基雜環之實例包括內醯胺、哌嗪酮、環氧乙基、環氧乙烷基、氮丙啶基、四氫呋喃基、二氧戊環基、吡咯啶基、哌啶基、吡唑啶基、咪唑啶基、四氫噻吩基、二硫基、噻唑啶基、四氫哌喃基、二氧雜環己烷基、嗎啉基、哌啶基、哌嗪基、四氫硫哌喃基、二噻烷基、硫嗎啉基、二氫呋喃基、2-咪唑啉基、2,3-吡咯啉基、吡唑啉基、二氫噻吩基、二氫哌喃基、哌喃基、四氫吡啶基、二氫吡啶基、四氫嘧啶基及二氫硫哌喃基，以及衍生自與苯基核心之稠合的相應基團，且更特定言之為嗎啉基、二氧雜環戊烷基、苯并噻唑啶基、吡咯啶基及苯并吡咯啶基環。The heterocyclic ring can be saturated or partially unsaturated and can contain one or more double bonds. It is therefore referred to as a heterocycloalkyl group . Examples of non-aromatic or heterocycloalkylheterocycles which may be mentioned include indoleamine, piperazinone, epoxyethyl, oxiranyl, aziridine, tetrahydrofuranyl, dioxolane, Pyrrolidinyl, piperidinyl, pyrazolyl, imidazolidinyl, tetrahydrothiophenyl, disulfide , thiazolidinyl, tetrahydropyranyl, dioxanyl, morpholinyl, piperidinyl, piperazinyl, tetrahydrothiopyranyl, dithiaalkyl, thiomorpholinyl, Hydrofuranyl, 2-imidazolinyl, 2,3-pyrrolinyl, pyrazolinyl, dihydrothienyl, dihydropentanyl, piperidyl, tetrahydropyridyl, dihydropyridyl, tetrahydrogen Pyrimidinyl and dihydrothiopyranyl, and corresponding groups derived from the condensation with a phenyl core, and more specifically morpholinyl, dioxolane, benzothiazolidinyl, pyrrole Pyridyl and benzopyrrolidinyl rings.

雜環烷基宜為包含4、5、6或7個碳原子且包含1、2或3個選自氧、氮及硫之雜原子的視情況橋接之環狀烷基，例如哌啶基、哌嗪基、.吡咯啶基、六亞甲基亞胺基、嗎啉基及1,1-二氧離子基四氫噻吩基。Heterocycloalkyl is preferably a optionally bridged cyclic alkyl group containing 4, 5, 6 or 7 carbon atoms and comprising 1, 2 or 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, for example piperidinyl, Piperazinyl, pyrrolidinyl, hexamethyleneimine, morpholinyl and 1,1-dioxainyltetrahydrothiophenyl.

該雜環亦可為芳族的及5員至10員，且因而可表示雜芳基。The heterocyclic ring may also be aromatic and from 5 to 10 members, and thus may represent a heteroaryl group.

可特別提及之雜芳基包括以下代表性基團：苯并咪唑基、苯并噻唑基、呋喃基、咪唑基、吲哚基、吲哚嗪基、異噁唑基、異喹啉基、異噻唑基、噁二唑基、吡嗪基、噠嗪基、吡唑基、吡啶基、嘧啶基、吡咯基、喹唑啉基、喹啉基、1,3,4-噻二唑基、噻唑基、噻吩基及***基。Heteroaryl groups which may especially be mentioned include the following representative groups: benzimidazolyl, benzothiazolyl, furyl, imidazolyl, indolyl, pyridazinyl, isoxazolyl, isoquinolinyl, Isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1,3,4-thiadiazolyl, Thiazolyl, thienyl and triazolyl.

雜芳基宜為包含2、3、4或5個碳原子且包含1、2或3個可選自氮原子、氧原子及硫原子之雜原子的環狀芳族基，當有雜原子中之兩者時，該等雜原子彼此獨立以致相同或不同，或當有雜原子中之三者時，該等雜原子彼此獨立以致相同或不同。可特別提及之實例包括吡啶基、吡咯基及呋喃基。The heteroaryl group is preferably a cyclic aromatic group containing 2, 3, 4 or 5 carbon atoms and containing 1, 2 or 3 hetero atoms which may be selected from a nitrogen atom, an oxygen atom and a sulfur atom, in the presence of a hetero atom In both cases, the heteroatoms are independent of each other so as to be the same or different, or when there are three of the heteroatoms, the heteroatoms are independent of one another so as to be the same or different. Examples which may be specifically mentioned include pyridyl, pyrrolyl and furyl.

當雜環經取代時，取代基可在一或多個包括於該雜環中之碳原子上及/或在適當時，在該雜環之雜原子上。當雜環包含若干個取代基時，其可攜帶於不同原子上或在適當時，存在於同一原子上。When a heterocyclic ring is substituted, the substituent may be on one or more of the carbon atoms included in the heterocyclic ring and/or, where appropriate, on the hetero atom of the heterocyclic ring. When a heterocyclic ring contains a plurality of substituents, it may be carried on a different atom or, where appropriate, on the same atom.

　保護基Pg： 首先能夠在合成期間保護諸如羥基或胺之反應性官能基且其次在合成結束時使完整反應性官能基再生之基團。保護基及保護與脫除保護基方法之實例在「Protective Groups in Organic Synthesis」,Greene等人，第2版(John Wiley & Sons,Inc.,New York)中給出；　脫離基： 可容易地藉由使異質鍵斷裂同時失去一電子對而自分子裂解出之基團。此基團因而可容易地在例如取代反應期間經另一基團置換。該等脫離基例如為鹵素或活化羥基，諸如甲烷磺酸酯基、苯磺酸酯基、對甲苯磺酸酯基、三氟甲磺酸酯基、乙酸酯基等。脫離基之實例及關於其製備之參考資料在「Advances in Organic Chemistry」,J. March,第3版，Wiley Interscience,第310-316頁中給出。 Protecting group Pg: A group which is capable of first protecting a reactive functional group such as a hydroxyl group or an amine during synthesis and secondly regenerating a complete reactive functional group at the end of the synthesis. Examples of protecting groups and methods of protecting and removing protecting groups are given in "Protective Groups in Organic Synthesis", Greene et al., 2nd Edition (John Wiley & Sons, Inc., New York); Release group: A group that can be easily cleaved from a molecule by breaking a hetero-bond while losing an electron pair. This group can thus be easily replaced by another group during, for example, the substitution reaction. The leaving groups are, for example, halogen or an activated hydroxyl group such as a methanesulfonate group, a benzenesulfonate group, a p-toluenesulfonate group, a triflate group, an acetate group, and the like. Examples of detachment groups and references for their preparation are given in "Advances in Organic Chemistry", J. March, 3rd edition, Wiley Interscience, pages 310-316.

在作為本發明之目標的式(I)化合物中，第一群化合物係由如下化合物構成，其中：A 表示CH或C(CH3 )，A 宜表示CH；及/或X 表示CH或N，X 宜表示CH；及/或R 1 、R 2 、R 3 及R 4 可相同或不同且彼此獨立地表示：‧　氫原子；‧　直鏈、分支鏈或環狀烷基，視情況經以下一或多個取代：○　鹵素原子；○ -OR9 ；○ -NR9 R'9 ；○ -CN；○ -C(O)OR9 ；○ -C(O)NR9 R9' ；○ -S(O)p R10 ；○ -S(O)2 NR9 R'9 ；●　基團-S(O)p R10 ；●　基團-OR10 ；●　鹵素原子；●　基團-N(R11 )C(O)R12 ；●　基團-N(R14 )-CH2 -C(O)NR15 R9 ，其中R 14 及R 15 與其所連接之原子一起形成雜環烷基，以便形成哌嗪酮且其中R 9 如下定義；●　基團-C(O)NR16 R17 ，其中R 16 及R 17 與其所連接之氮原子一起形成雜環烷基，以便有利地形成哌啶基或吡咯啶基，●　基團-T-U ，其中：■　T 表示：○　單鍵，○　直鏈或分支鏈伸烷基；○　基團-C(O)-；○　基團-S(O)p -，其中p如下定義，或○基團-O-(CH2 )n -，其中n如下定義，且U 表示包含一或多個選自N、O及S(O)p之雜原子的雜環，其中p如下定義，該雜環為飽和、不飽和或芳族的，視情況經1、2或若干個選自以下之取代基單取代或二取代或多取代：基團-OR7 ，鹵素原子，基團-C(O)R7 ，直鏈、分支鏈或環狀烷基，視情況經一或多個選自鹵素原子、基團-OR10 、基團-NR9 R'9 及基團-CN之取代基取代；飽和、不飽和或芳族雜環，視情況經一或多個選自鹵素原子、基團-OR9 、基團-NR9 R'9 及烷基之取代基取代，該等烷基視情況經一或多個鹵素原子取代；應瞭解，當U 為包含至少一個氮原子之雜環烷基時，該取代基宜選自：基團-C(O)R7 ；及直鏈、分支鏈或環狀烷基，視情況經一或多個選自鹵素原子、基團-OR10 、基團-NR9 R'9 及基團-CN之取代基取代；且該取代基宜由該氮原子所攜帶，或■T 表示：○基團-C(O)-；○基團-S(O)2 -；或○基團-O-(C2-C3)伸烷基-；且U 表示基團-NR9 R'9 ；或■T 表示：○基團-C(O)-；或○基團-O-(C2-C3)伸烷基-；且U 表示基團-OR9 ；或■T 表示：○直鏈或分支鏈伸烷基；或○基團-O-(C2-C3)伸烷基-；且U 表示基團-NR8 R9 ；或者選自R1 、R2 、R3 及R4 之兩個相鄰基團與攜帶其之兩個碳連接並形成視情況經一或多個直鏈、分支鏈或環狀烷基取代之飽和、不飽和或芳族雜環，該等烷基視情況經一或多個選自鹵素原子、基團-OR10 及基團-NR9 R'9 之取代基取代，及/或R 5 表示：‧直鏈或分支鏈烷基，視情況經一或多個選自鹵素原子、基團-OR9 、基團-NR9 R'9 、基團-CN、基團-C(O)NR9 R9' 、基團-S(O)p R10 及視情況經基團-NR9 R'9 取代之環烷基的取代基取代，‧環烷基，視情況經基團-NR9 R'9 取代，‧烷氧基-OR9 ，‧芳基，視情況經一或多個選自基團(C1-C3)烷基、鹵素原子及基團-O-(C1-C3)烷基之取代基取代，或‧基團-(CH2 )t -R13 ，R 5 宜表示(i)直鏈或分支鏈烷基，視情況經一或多個選自鹵素原子、基團-OR9 、基團-NR9 R'9 及環烷基之取代基取代，(ii)環烷基，(iii)芳基，視情況經一或多個選自基團(C1-C3)烷基、鹵素原子及基團-O-(C1-C3)烷基之取代基取代，或(iv)基團-(CH2 )t -R13 ，及/或R 6 表示氫原子或直鏈、分支鏈或環狀烷基，R 6 宜表示氫原子，及/或R 7 表示氫原子或視情況經一或多個選自鹵素原子、基團-OR9 及基團-NR9 R'9 之取代基取代的直鏈、分支鏈或環狀烷基；及/或R 8 表示雜芳基，宜為吡啶；及/或R 9 及R' 9 彼此獨立地表示氫原子或直鏈、分支鏈或環狀烷基；及/或R 10 表示氫原子或視情況經一或多個鹵素原子取代之直鏈、分支鏈或環狀烷基，及/或R 11 及R 12 彼此獨立地表示氫原子或視情況經一或多個選自鹵素原子、基團-OR9 及基團-NR9 R'9 之取代基取代的直鏈、分支鏈或環狀烷基，或R 11 及R 12 與其所連接之原子一起形成雜環烷基，以便形成內醯胺；及/或R 13 表示視情況經一或多個選自直鏈、分支鏈或環狀烷基之取代基取代的雜芳基或雜環烷基，應瞭解當該雜環烷基包含至少一個氮原子時，此原子可視情況攜帶該取代基，R 13 宜為四氫呋喃基，及/或t 表示1或2，及/或n 表示0、1、2或3，及/或p 表示0、1或2，及/或其呈酸、鹼或與酸或鹼形成之加成鹽形式，以及呈水合物或溶劑合物形式。In the compound of the formula (I) which is the object of the present invention, the first group of compounds is composed of a compound wherein A represents CH or C(CH 3 ), A preferably represents CH; and/or X represents CH or N, X preferably represents CH; and/or R 1 , R 2 , R 3 and R 4 may be the same or different and independently of each other: ‧ a hydrogen atom; ‧ a straight chain, a branched chain or a cyclic alkyl group, as the case may be Or a plurality of substitutions: ○ halogen atom; ○ -OR 9 ; ○ -NR 9 R'9; ○ -CN; ○ -C(O)OR 9 ; ○ -C(O)NR 9 R 9' ; ○ -S (O) p R 10 ; ○ -S(O) 2 NR 9 R'9; ● group -S(O) p R 10 ; ● group -OR 10 ; ● halogen atom; ● group -N (R 11 )C(O)R 12 ;● group -N(R 14 )-CH 2 -C(O)NR 15 R 9 , wherein R 14 and R 15 together with the atom to which they are attached form a heterocycloalkyl group, Forming piperazinone and wherein R 9 is as defined below; • group -C(O)NR 16 R 17 , wherein R 16 and R 17 together with the nitrogen atom to which they are attached form a heterocycloalkyl group to advantageously form a piperidinyl group or pyrrolidinyl, ● group -TU, wherein: ■ T represents: ○ a single bond, ○ a straight-chain or branched alkylene group; yl ○ -C (O) -; ○ group -S (O) p -, wherein p is as defined below, or a group ○ -O- (CH 2) n -, wherein n is as defined below, and U represents comprises one or more a heterocyclic ring selected from the group consisting of N, O and S(O)p, wherein p is as defined below, the heterocyclic ring being saturated, unsaturated or aromatic, optionally substituted by 1, 2 or several selected from the group consisting of Mono- or di- or poly-substitution: Group -OR 7 , Halogen atom, Group -C(O)R 7 , a straight chain, a branched chain or a cyclic alkyl group, optionally substituted with one or more substituents selected from the group consisting of a halogen atom, a group -OR 10 , a group -NR 9 R' 9 and a group -CN; a saturated, unsaturated or aromatic heterocyclic ring, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a group -OR 9 , a group -NR 9 R' 9 and an alkyl group, as appropriate Substituted by one or more halogen atoms; it is understood that when U is a heterocycloalkyl group containing at least one nitrogen atom, the substituent is preferably selected from: Group -C(O)R 7 ; a straight chain, a branched chain or a cyclic alkyl group, optionally substituted with one or more substituents selected from the group consisting of a halogen atom, a group -OR 10 , a group -NR 9 R' 9 and a group -CN; and the substitution Suitably carried by the nitrogen atom, or ■ T represents: ○ group -C(O)-; ○ group -S(O) 2 -; or ○ group -O-(C2-C3) alkylene -; and U represents a group -NR 9 R'9; or ■ T represents: ○ group -C(O)-; or ○ group -O-(C2-C3)alkyl-; and U represents a group a group -OR 9 ; or ■ T represents: o a linear or branched alkyl group; or a ○ group -O-(C2-C3)alkyl-; and U represents a group -NR 8 R 9 ; Two adjacent groups from R1 , R2 , R3 and R4 are bonded to the two carbons carrying them and form saturated, unsaturated or aromatic groups which are optionally substituted by one or more linear, branched or cyclic alkyl groups. a heterocyclic ring, which is optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a group -OR 10 and a group -NR 9 R' 9 and/or R 5 represents: ‧ straight chain or a branched alkyl group, optionally, one or more selected from the group consisting of a halogen atom, a group -OR 9 , a group -NR 9 R' 9 , a group -CN, a group -C(O)NR 9 R 9' , group-S(O ) P R 10 and optionally substituted with a group -NR 9 R '9 of substituted cycloalkyl substituents, cycloalkyl ‧ per group, optionally substituted with a group -NR 9 R' 9 substituted, an alkoxy group -OR ‧ per 9 , ‧ aryl, optionally substituted by one or more substituents selected from the group consisting of a (C1-C3)alkyl group, a halogen atom and a group -O-(C1-C3)alkyl group, or a ‧ group (CH 2 ) t -R 13 , R 5 preferably denotes (i) a straight-chain or branched alkyl group, optionally containing one or more selected from the group consisting of a halogen atom, a group -OR 9 , a group -NR 9 R' 9 And a substituent of a cycloalkyl group, (ii) a cycloalkyl group, (iii) an aryl group, optionally one or more selected from the group consisting of a (C1-C3) alkyl group, a halogen atom and a group -O-( Substituting a C1-C3) alkyl group, or (iv) a group -(CH 2 ) t -R 13 , and/or R 6 represents a hydrogen atom or a straight chain, a branched chain or a cyclic alkyl group, and R 6 is preferably a hydrogen atom, and/or R 7 represents a hydrogen atom or, as the case may be, a linear or branched chain substituted with one or more substituents selected from the group consisting of a halogen atom, a group -OR 9 and a group -NR 9 R' 9 cyclic alkyl group; and / or R 8 represents a heteroaryl group, as appropriate pyridine; and / or R 9 and R '9 each independently represent a hydrogen atom or a linear, branched or cyclic Group; and / or R 10 represents a hydrogen atom or optionally substituted with one or more halogen atoms of straight-chain, branched or cyclic alkyl group, and / or R 11 and R 12 each independently represent a hydrogen atom or optionally a linear, branched or cyclic alkyl group substituted with one or more substituents selected from the group consisting of a halogen atom, a group -OR 9 and a group -NR 9 R' 9 or R 11 and R 12 attached thereto The atoms together form a heterocycloalkyl group to form an indoleamine; and/or R 13 represents a heteroaryl or heterocyclic ring optionally substituted with one or more substituents selected from a linear, branched or cyclic alkyl group. Alkyl, it is understood that when the heterocycloalkyl group contains at least one nitrogen atom, the atom may optionally carry the substituent, R 13 is preferably tetrahydrofuranyl, and/or t represents 1 or 2, and/or n represents 0, 1, 2 or 3, and/or p represents 0, 1 or 2, and/or it is in the form of an acid, a base or an addition salt formed with an acid or a base, and in the form of a hydrate or a solvate.

在作為本發明之目標的式(I)化合物中，第二群化合物係由如下化合物構成，其中：　A 表示CH，　X 表示CH、C(烷基)或N，X 宜表示CH， R 1 、R 2 、R 3 及R 4 可相同或不同且彼此獨立地表示：○氫原子，○直鏈、分支鏈或環狀烷基，視情況經以下一或多個取代：鹵素原子、基團-OR9 及-NR9 R'9 ，其中R9 及R'9 彼此獨立地表示氫原子或直鏈、分支鏈或環狀烷基，○基團-S(O)p R10 或基團-OR10 ，其中R10 表示氫原子或視情況經一或多個鹵素原子取代的直鏈、分支鏈或環狀烷基，且p表示0、1或2，○鹵素原子，○基團-N(R11 )C(O)R12 ，其中R11 及R12 彼此獨立地表示氫原子或直鏈、分支鏈或環狀烷基，或R11 及R12 與其所連接之原子一起形成雜環烷基，以便形成內醯胺；○　基團-T-U ，其中■　T 表示：‧　單鍵，‧　直鏈或分支鏈伸烷基，‧　基團-C(O)-，‧　基團-S(O)p ，其中p表示0、1或2，‧　基團-O-(CH2 )n -，其中n表示0、1、2或3，且U 表示包含一或多個選自N、O及S(O)p之雜原子的雜環，其中p表示0、1或2，該雜環具有下式：In the compound of the formula (I) which is the object of the present invention, the second group of compounds is composed of the following compounds, wherein: A means CH, X represents CH, C (alkyl) or N, and X preferably represents CH, R 1 , R 2 , R 3 and R 4 may be the same or different and independently of each other: ○ a hydrogen atom, ○ a linear chain, a branched chain or a cyclic alkyl group, optionally substituted by one or more of the following: a halogen atom, a group -OR 9 and -NR 9 R' 9 , wherein R 9 and R' 9 independently of each other represent a hydrogen atom or a straight chain, a branched chain or a cyclic alkyl group, and the group ○-S(O) p R 10 or a group -OR 10 , wherein R 10 represents a hydrogen atom or, as the case may be, a linear, branched or cyclic alkyl group substituted by one or more halogen atoms, and p represents 0, 1 or 2, ○ halogen atom, ○ group a group -N(R 11 )C(O)R 12 , wherein R 11 and R 12 independently of each other represent a hydrogen atom or a straight chain, a branched chain or a cyclic alkyl group, or R 11 and R 12 together with the atom to which they are attached Forming a heterocycloalkyl group to form an indoleamine; ○ group -TU , wherein ■ T represents: ‧ a single bond, ‧ a straight or branched alkyl group, ‧ a group -C(O)-, a ‧ group -S(O) p , wherein p represents 0, 1 or 2, ‧ a group -O-(CH 2 ) n -, wherein n represents 0, 1, 2 or 3, and U represents one or more selected from a heterocyclic ring of a hetero atom of N, O and S(O)p, wherein p represents 0, 1 or 2, the heterocyclic device The following formula:

其中●*表示U連接至T之位置；●　M 1 表示C或N原子；●　M 2 及M 3 可相同或不同且表示C、N或O原子或S(O)p，其中p=0、1或2；●　M 4 表示C、C(=O)、N、O或S(O)p原子，其中p=0、1或2；M i 各可相同或不同且表示C、C(=O)、N、O或S(O)p原子，其中p=0、1或2；●　i =0、1、2或3；應瞭解在適當時若價數可取及/或相鄰M1 、M2 、M3 、M4 或Mi 可經由雙鍵連接，則M1 、M2 、M3 、M4 或Mi 各可視情況經取代；該雜環U 為飽和、不飽和或芳族的，視情況經1、2或若干個選自以下之取代基單取代或二取代或多取代：○　基團-OR7 ，其中R7 表示氫原子或直鏈、分支鏈或環狀烷基，○　鹵素原子，○　基團-COR7 ，其中R7 表示氫原子或直鏈、分支鏈或環狀烷基，○　直鏈、分支鏈或環狀烷基，宜為甲基、乙基或環丙基，視情況經一或多個鹵素原子取代，○　飽和、不飽和或芳族雜環，尤其為包含N之雜環，宜為嗎啉基、吡咯啶基或哌啶基，視情況經一或多個選自鹵素原子及視情況經一或多個鹵素原子取代之烷基之基團取代；或者R 1 、R 2 、R 3 及R 4 之中的兩個相鄰基團與攜帶其之兩個碳連接並形成視情況經一或多個直鏈、分支鏈或環狀烷基取代之飽和、不飽和或芳族雜環，該等烷基視情況經至少一個選自基團-NR9 R'9 之基團取代，其中R9 及R'9 彼此獨立地表示氫原子或烷基，該雜環與環(Ar)稠合，　R 5 表示(i)直鏈或分支鏈烷基，視情況經一或多個選自鹵素原子、環烷基、基團-NR9 R'9 (其中R9 及R'9 彼此獨立地表示氫原子或烷基)及基團-OR9 (其中R9 表示氫原子或烷基)之取代基取代，(ii)芳基，視情況經一或多個選自基團(C1-C3)烷基、鹵素原子及基團-O-(C1-C3)烷基之取代基取代，且　R 6 表示氫原子或直鏈、分支鏈或環狀烷基，其呈酸、鹼或與酸或鹼形成之加成鹽形式，以及呈水合物或溶劑合物形式。Wherein ** indicates the position at which U is connected to T; ● M 1 represents a C or N atom; ● M 2 and M 3 may be the same or different and represent a C, N or O atom or S(O)p, where p=0, 1 or 2; ● M 4 represents a C, C(=O), N, O or S(O)p atom, wherein p=0, 1 or 2; M i may each be the same or different and represent C, C (= O), N, O or S(O)p atom, where p = 0, 1 or 2; ● i = 0, 1, 2 or 3; it should be understood that if appropriate, the valence may or may be adjacent to M 1 , M 2 , M 3 , M 4 or M i may be linked via a double bond, and then M 1 , M 2 , M 3 , M 4 or M i may each be optionally substituted; the heterocyclic ring U is saturated, unsaturated or aromatic Or a di- or poly-substituted group of 1, 2 or several substituents selected from the group consisting of: ○ group -OR 7 , wherein R 7 represents a hydrogen atom or a straight chain, a branched chain or a cyclic alkane Base, ○ halogen atom, ○ group -COR 7 , wherein R 7 represents a hydrogen atom or a straight chain, a branched chain or a cyclic alkyl group, ○ a straight chain, a branched chain or a cyclic alkyl group, preferably a methyl group or an ethyl group Or a cyclopropyl group, optionally substituted by one or more halogen atoms, ○ a saturated, unsaturated or aromatic heterocyclic ring, especially a heterocyclic ring containing N Is suitably morpholinyl, pyrrolidinyl or piperidinyl, optionally substituted with one or more substituents selected from halogen atoms and optionally substituted with one or more substituents of halogen atoms of groups; or R 1, R 2 And two adjacent groups of R 3 and R 4 are bonded to the two carbons carrying the same and form a saturated, unsaturated or aromatic group which is optionally substituted by one or more linear, branched or cyclic alkyl groups. a heterocyclic ring, which is optionally substituted with at least one group selected from the group -NR 9 R' 9 wherein R 9 and R' 9 independently of each other represent a hydrogen atom or an alkyl group, the heterocyclic ring and the ring (Ar) fused, R 5 represents (i) a linear or branched alkyl group, optionally selected from one or more selected from the group consisting of a halogen atom, a cycloalkyl group, and a group -NR 9 R' 9 (wherein R 9 and R' 9 are independently of each other a hydrogen atom or an alkyl group and a substituent of the group -OR 9 (wherein R 9 represents a hydrogen atom or an alkyl group), (ii) an aryl group, optionally selected from one or more groups (C1-C3) Substituted with an alkyl group, a halogen atom, and a substituent of the group -O-(C1-C3)alkyl, and R 6 represents a hydrogen atom or a linear, branched or cyclic alkyl group which is in the form of an acid, a base or an addition salt formed with an acid or a base, and is in the form of a hydrate or a solvate.

在作為本發明之目標的式(I)化合物中，另一群化合物係由對應於下式(I')之化合物構成：In the compound of the formula (I) which is the object of the present invention, another group of compounds is composed of a compound corresponding to the following formula (I'):

其中： R 1 表示：●　氫原子，●　直鏈、分支鏈或環狀烷基，視情況經一或多個選自以下之取代基取代：鹵素原子、基團-NR9 R'9 ，其中R9 及R'9 彼此獨立地表示氫原子或烷基，宜為甲基，● -OR10 ，其中R10 表示氫原子或視情況經一或多個鹵素原子取代之直鏈、分支鏈或環狀烷基，●　鹵素原子，●　基團-T-U ，其中T 表示：○　單鍵，○　伸烷基，宜為基團-(CH2 )1-3 -，○　基團-C(O)-，○　基團-O-(CH2 )n -，其中n表示0、1、2或3，且U 表示飽和、不飽和或芳族雜環，視情況經宜選自以下之取代基單取代或二取代：○　鹵素原子，○　基團-COR7 ，其中R7 表示氫原子或直鏈、分支鏈或環狀烷基，宜為甲基，○直鏈、分支鏈或環狀烷基，宜為甲基、乙基或環丙基，該烷基視情況經一或多個鹵素取代，○雜環，宜為飽和的，包含氮原子，宜為嗎啉基、吡咯啶基或哌啶基，該雜環視情況經一或多個選自鹵素原子之基團取代； R2 、R3 及R4 可相同或不同且獨立地表示：○氫原子，○直鏈、分支鏈或環狀烷基，視情況經一或多個選自以下之取代基取代：鹵素原子及基團-NR9 R'9 ，其中R9 及R'9 彼此獨立地表示氫原子或烷基，宜為甲基，○基團-OR10 ，其中R10 表示氫原子或視情況經一或多個鹵素原子取代之烷基，○鹵素，○基團-T-U，其中T表示一鍵且U表示嗎啉基，或 R 1 及R 2 與攜帶其之兩個碳原子連接並形成選自哌啶、噻唑、四氫呋喃及二噁烷之雜環，該雜環視情況經直鏈、分支鏈或環狀烷基取代，該烷基視情況經-NR9 R'9 取代，其中R9 及R'9 彼此獨立地表示氫原子或甲基，該雜環與環(Ar)稠合， R5 表示(i)包含1至5個碳原子之直鏈或分支鏈烷基，宜為乙基，視情況經一或多個選自鹵素原子(宜為氟原子)或基團-OH之取代基取代，(ii)芳基，視情況經一或多個選自基團(C1-C3)烷基(宜為甲基)、鹵素原子(宜為氟原子)及基團-O-(C1-C3)烷基(宜為甲氧基)之取代基取代，其呈酸、鹼或與酸或鹼形成之加成鹽形式，以及呈水合物或溶劑合物形式。在上述式(I)或(I')化合物中，可提及如下化合物，其中： A 表示CH；及/或 X 表示CH；及/或 R 1 、R 2 、R 3 及R 4 不全表示氫原子；及/或 R 1 不為氫原子；及/或 R 1 係選自：among them: R 1 represents: a hydrogen atom, a linear, branched or cyclic alkyl group, optionally substituted with one or more substituents selected from the group consisting of a halogen atom, a group -NR 9 R' 9 , wherein R 9 and R '9 independently represent a hydrogen atom or an alkyl group is suitably a methyl, ● -OR 10, wherein R 10 represents a hydrogen atom or optionally substituted with one or more halogen atoms of straight-chain, branched or cyclic Alkyl, ● halogen atom, ● group -TU , wherein T represents: ○ single bond, ○ alkyl group, preferably a group -(CH 2 ) 1-3 -, ○ group -C(O)-, o a group -O-(CH 2 ) n -, wherein n represents 0, 1, 2 or 3, and U represents a saturated, unsaturated or aromatic heterocyclic ring, optionally substituted by a substituent selected from the group consisting of or Disubstituted: ○ halogen atom, ○ group -COR 7 , wherein R 7 represents a hydrogen atom or a linear, branched or cyclic alkyl group, preferably a methyl group, ○ straight chain, branched chain or cyclic alkyl group, preferably Is a methyl, ethyl or cyclopropyl group, the alkyl group optionally substituted by one or more halogens, ○ heterocyclic ring, preferably saturated, containing a nitrogen atom, preferably morpholinyl, pyrrolidinyl or piperidinyl , the heterocyclic ring With one or more substituent groups selected from halogen atoms; R 2 , R 3 and R 4 may be the same or different and independently represent: ○ hydrogen atom, ○ straight chain, branched chain or cyclic alkyl group, optionally substituted by one or more substituents selected from the group consisting of halogen atoms and groups —NR 9 R′ 9 , wherein R 9 and R′ 9 independently of each other represent a hydrogen atom or an alkyl group, preferably a methyl group, and a group —OR 10 , wherein R 10 represents a hydrogen atom or, as the case may be, one or more a halogen-substituted alkyl group, ○ halogen, ○ group - TU, wherein T represents a bond and U represents a morpholinyl group, or R 1 and R 2 are bonded to two carbon atoms carrying them and form a heterocyclic ring selected from the group consisting of piperidine, thiazole, tetrahydrofuran and dioxane, which ring is optionally substituted by a linear, branched or cyclic alkyl group. The alkyl group is optionally substituted by -NR 9 R' 9 , wherein R 9 and R' 9 independently of each other represent a hydrogen atom or a methyl group, and the heterocyclic ring is fused to the ring (Ar), R5 represents (i) a linear or branched alkyl group having 1 to 5 carbon atoms, preferably an ethyl group, optionally substituted by one or more halogen atoms (preferably a fluorine atom) or a group -OH Substituent, (ii) aryl, optionally, one or more selected from the group consisting of a (C1-C3)alkyl group (preferably a methyl group), a halogen atom (preferably a fluorine atom), and a group -O-(C1) -C3) Substituted by a substituent of an alkyl group (preferably methoxy) which is in the form of an acid, a base or an addition salt formed with an acid or a base, and is in the form of a hydrate or a solvate. Among the above compounds of the formula (I) or (I'), the following compounds may be mentioned, wherein: A represents CH; and/or X represents CH; and/or R 1 , R 2 , R 3 and R 4 are not all represented by a hydrogen atom; and/or R 1 is not a hydrogen atom; and/or R 1 is selected from:

R5 表示(i)直鏈或分支鏈烷基，宜為乙基，(ii)芳基，視情況經一或多個選自基團(C1-C3)烷基(宜為甲基)、鹵素原子(宜為氟原子)之取代基取代；及/或 U 表示飽和、不飽和或芳族雜環，視情況經單取代或二取代，包含至少一個氮原子及/或一個氧原子，及/或 U 表示包含至少一個氮原子之飽和雜環；及/或 U 表示選自以下之雜環：○氮雜環丁烷基，宜為氮雜環丁烷-1-基或氮雜環丁烷-3-基；○　吡咯啶基，宜為吡咯啶-1-基或吡咯啶-3-基；○　酮基吡咯啶基，宜為2-酮基吡咯啶-1-基；○　哌啶基，宜為哌啶-1-基、哌啶-2-基或哌啶-4-基，尤其宜為哌啶-1-基或哌啶-4-基；○　1,2,3,6-四氫吡啶基，宜為1,2,3,6-四氫吡啶-4-基；○　吡啶基，宜為吡啶-2-基；○　哌嗪基，宜為哌嗪-1-基；○　二氮雜環庚烷基，宜為二氮雜環庚烷-1-基；○　嗎啉基，宜為嗎啉-4-基或嗎啉-3-基，尤其為4-(R)-1-嗎啉-3-基，尤其宜為嗎啉-4-基；○　1,1-二酮基-1λ6-硫嗎啉-4-基。 R5 represents (i) a straight or branched alkyl group, preferably an ethyl group, (ii) an aryl group, optionally one or more selected from the group consisting of a (C1-C3) alkyl group (preferably a methyl group), a halogen. Substituted by a substituent of an atom (preferably a fluorine atom); and/or U represents a saturated, unsaturated or aromatic heterocyclic ring, optionally substituted or disubstituted, containing at least one nitrogen atom and/or one oxygen atom, and/or U represents a saturated heterocyclic ring containing at least one nitrogen atom; and/or U represents a heterocyclic ring selected from the group consisting of ○ azetidinyl, preferably azetidin-1-yl or azetidin-3-yl; ○ pyrrolidinyl, preferably pyrrolidine-1 -yl or pyrrolidin-3-yl; o ketopyrrolidinyl, preferably 2-ketopyrrolidin-1-yl; o piperidinyl, preferably piperidin-1-yl, piperidin-2-yl Or piperidin-4-yl, especially preferably piperidin-1-yl or piperidin-4-yl; ○ 1,2,3,6-tetrahydropyridyl, preferably 1,2,3,6-tetra Hydropyridin-4-yl; ○ pyridyl, preferably pyridin-2-yl; ○ piperazinyl, preferably piperazin-1-yl; oxadiazepine, preferably diazepane -1-yl; ○ morpholinyl, preferably morpholin-4-yl or morpholin-3-yl, especially 4-(R)-1-morpholin-3-yl, especially preferably morpholine-4 - group; ○ 1,1-dione-1λ6-thiomorpholin-4-yl.

在作為本發明之目標的式(I)化合物中，可按下表之化合物的順序特別提及以下化合物：7-胺基-8-乙基-2-(4-羥基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(苯并噻唑-6-基胺基)-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[4-(環丙烷羰基甲基胺基)苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(4-甲基哌嗪-1-羰基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(4-環戊氧基苯基胺基)-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(4-乙基哌嗪-1-基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-[4-(4-吡咯啶-1-基哌啶-1-基)苯基胺基]-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-[4-(4-吡咯啶-1-基哌啶-1-基)苯基胺基]-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-[4-(4-吡咯啶-1-基哌啶-1-基)苯基胺基]-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-環戊基-2-(4-嗎啉-4-基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-[4-(哌啶-1-磺醯基)苯基胺基]-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；2-[4-(4-乙醯基哌嗪-1-基)苯基胺基]-7-胺基-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-(4-嗎啉-4-基苄基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-(喹啉-3-基胺基)-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-[4-(3-哌啶-1-基丙氧基)苯基胺基]-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-(3,4,5,6-四氫-2H-[1,2']聯吡啶-5'-基胺基)-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-[4-(2-酮基吡咯啶-1-基)苯基胺基]-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-(喹啉-6-基胺基)-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-(3-嗎啉-4-基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(2,3-二氫苯并[1,4]二氧雜環己烯(dioxin)-6-基胺基)-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-(3-氟-4-羥基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-(3-甲基硫基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-(4-嗎啉-4-基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-(4-嗎啉-4-基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-(4-嗎啉-4-基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-(2-氟苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[4-(4,4-二氟[1,4']聯哌啶-1'-基)-2-甲氧基苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺7-胺基-8-乙基-2-[2-甲氧基-4-(4-三氟甲基[1,4']聯哌啶-1'-基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺7-胺基-2-{4-[4-(3,3-二氟吡咯啶-1-基)哌啶-1-基]-2-甲氧基苯基胺基}-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺7-胺基-8-乙基-2-[4-(4-乙基哌嗪-1-基)-2-氟-6-甲氧基苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[4-(1-環丙基哌啶-4-基)-2-甲氧基苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(2-二甲基胺基甲基烷-6-基胺基)-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[5-氯-4-(4-環丙基哌嗪-1-基)-2-甲氧基苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[2-甲氧基-4-(4-嗎啉-4-基哌啶-1-基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[4-(4-環丙基哌嗪-1-基)-2-二氟甲氧基苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[4-(4-環丙基哌嗪-1-基)-2-甲氧基苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[2-氯-4-(4-乙基哌嗪-1-基)苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(4-乙基哌嗪-1-基)-3-三氟甲基苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-(4-嗎啉-4-基甲基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-{4-[4-(3,3,3-三氟丙基)哌嗪-1-基]苯基胺基}-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(4-乙基哌嗪-1-基)-3-氟苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；6-(4-嗎啉-4-基苯基胺基)-9-酮基-1,3,4,9-四氫-2H-1,4a,5,7-四氮雜-菲-10-甲醯胺；7-胺基-8-乙基-2-[4-(4-乙基哌嗪-1-基)-2-甲氧基苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(1-甲基哌啶-4-基甲氧基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[4-(4-環丙基哌嗪-1-基)苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(4-乙基哌嗪-1-基)-2-甲基苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(4-乙基[1,4]二氮雜環庚烷-1-基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；8-(4-嗎啉-4-基苯基胺基)-5-酮基-1,2,3,5-四氫-3,7,9,9b-四氮雜-環戊幷(cyclopenta)[a]萘-4-甲醯胺；7-胺基-8-乙基-5-酮基-2-{4-[2-(3-三氟甲基哌啶-1-基)乙基]苯基胺基}-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(3-嗎啉-4-基丙基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-{4-[1-(2,2,2-三氟乙基)哌啶-4-基]苯基胺基}-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-(4-(S)-1-嗎啉-3-基甲基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-異丁基-2-[4-(2-嗎啉-4-基乙基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-{4-[2-(3-氟氮雜環丁烷-1-基)乙基]苯基胺基}-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[4-(2-嗎啉-4-基乙基)苯基胺基]-5-酮基-8-丙基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(2-羥基乙基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-(4-羥乙基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-(2-甲基-1,2,3,4-四氫異喹啉-6-基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-{4-[2-(1,1-二酮基-1λ6-硫嗎啉-4-基)乙基]苯基胺基}-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-{4-[2-(4-甲基-3-酮基哌嗪-1-基)乙基]苯基胺基}-5-酮基-5，8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-{4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-{4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(4-二甲基胺基甲基苯基胺基)-5-酮基-8-(2,2,2-三氟乙基)-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[3-氯-4-(4-吡咯啶-1-基哌啶-1-基)苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[3-氯-4-(4-吡咯啶-1-基哌啶-1-基)苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-(4-吡啶-2-基甲基苯基胺基)-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-{4-[2-(3,3-二氟吡咯啶-1-基)乙基]苯基胺基}-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-(4-吡咯啶-3-基苯基胺基)-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-(4-吡咯啶-3-基苯基胺基)-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-[4-(2-哌啶-1-基乙基)苯基胺基]-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[4-(2-嗎啉-4-基乙基)苯基胺基]-5-酮基-8-(2,2,2-三氟乙基)-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-{4-[2-(4,4-二氟哌啶-1-基)乙基]苯基胺基}-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(1-甲基吡咯啶-3-基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-{4-[2-(3,3-二氟哌啶-1-基)乙基]苯基胺基}-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-(3-甲氧基-丙基)-2-[4-(2-嗎啉-4-基乙基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(1-甲基哌啶-3-基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(4-二甲基胺基甲基苯基胺基)-8-異丙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(4-二甲基胺基甲基苯基胺基)-8-異丙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-(4-哌啶-3-基苯基胺基)-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-(1,2,3,4-四氫異喹啉-7-基胺基)-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-(1,2,3,4-四氫異喹啉-7-基胺基)-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-(1,2,3,4-四氫異喹啉-6-基胺基)-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(1-甲基哌啶-4-基氧基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(2-嗎啉-4-基乙氧基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(3-二甲基胺基甲基苯基胺基)-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-[4-(4-吡咯啶-1-基哌啶-1-基)苯基胺基]-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-[4-(哌啶-4-基氧基)苯基胺基]-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-(3-胺基丙基)-2-(4-嗎啉-4-基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(2-嗎啉-4-基乙基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(4-二甲基胺基甲基苯基胺基)-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(1-乙基哌啶-4-基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-(4-哌啶-4-基苯基胺基)-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[3-氯-4-(4-乙基哌嗪-1-基)苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[3-甲氧基-4-(3-哌啶-1-基丙氧基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-{4-[2-(4-三氟甲基哌啶-1-基)乙基]苯基胺基}-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-{4-[2-(順-2,6-二甲基嗎啉-4-基)乙基]苯基胺基}-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(4-二乙基胺基甲基苯基胺基)-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(4-二甲基胺基甲基苯基胺基)-8-(3-甲氧基-丙基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(4-乙基哌嗪-1-基)-2-氟苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-{4-[1-(2-氰基乙基)哌啶-4-基]苯基胺基}-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-{4-[1-(3-氟丙基)哌啶-4-基]苯基胺基}-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲酸醯胺；7-胺基-8-乙基-2-[4-(4-乙基哌嗪-1-基)-3-甲基苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[4-(4-環丙基哌嗪-1-基)-2-乙基苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；(±)-7-胺基-2-反-[4-(2-二甲基胺基環丙基)苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[4-(4-環丙基哌嗪-1-基)-5-氟-2-甲氧基苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[4-(4-環丙基哌嗪-1-基)-3-氟-2-甲氧基苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[4-(4-環丙基哌嗪-1-基)-2-乙氧基苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-(4-丙基苯基胺基)-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-(4-丙氧基苯基胺基)-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-(6-甲氧基吡啶-3-基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-(4-氟苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-(4-甲氧基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(苯并[1,3]二氧雜環戊烯-5-基胺基)-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-(4-哌啶-1-基苯基胺基)-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；8-乙基-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-7-甲基胺基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-異丁基-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-環丙基甲基-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-(2-甲氧基乙基)-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-5-酮基-8-(四氫呋喃-2-基甲基)-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-{4-[1-(3,3,3-三氟丙基)氮雜環丁烷-3-基]苯基胺基}-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-{5-氟-2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-8-異丁基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-[4-(1,2,3,6-四氫吡啶-4-基)苯基胺基]-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(2-甲氧基-4-哌啶-4-基苯基胺基)-5-酮基-8-苯基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-(2-羥基乙基)-2-(2-甲氧基-4-哌啶-4-基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-5-酮基-8-噻唑-2-基甲基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-5-酮基-8-噻唑-5-基甲基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-(2-羥基-2-甲基丙基)-2-(2-甲氧基-4-哌啶-4-基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；8-(2-乙醯基胺基乙基)-7-胺基-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-(2-胺基乙基)-2-(4-嗎啉-4-基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(4-嗎啉-4-基苯基胺基)-5-酮基-8-吡咯啶-3-基甲基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(4-乙基哌嗪-1-基)-2-羥基苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(4-嗎啉-4-基苯基胺基)-5-酮基-8-哌啶-4-基甲基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(2-甲氧基-4-嗎啉-4-基苯基胺基)-5-酮基-8-吡咯啶-3-基甲基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-(2-甲氧基-4-哌啶-4-基苯基胺基)-4-甲基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-5-酮基-8-噻吩-2-基甲基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-異丁基-2-[2-甲氧基-4-(4-嗎啉-4-基哌啶-1-基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(4-嗎啉-4-基苯基胺基)-5-酮基-8-吡咯啶-2-基甲基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)-1,2,3,6-四氫吡啶-4-基]苯基胺基}-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[4-(4-乙基哌嗪-1-基)-2-甲氧基苯基胺基]-8-(2-羥基-2-甲基丙基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-(2-羥基-2-甲基丙基)-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-(2-羥基-2-甲基丙基)-2-[4-(4-乙基哌啶-1-基)-2-甲氧基苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[4-(1-環丙基哌啶-4-基)-2-甲氧基苯基胺基]-8-(2-羥基-2-甲基丙基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-(2-羥基-2-甲基丙基)-2-{2-甲氧基-4-[1-(2-甲氧基乙基)哌啶-4-基]苯基胺基}-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[2-甲氧基-4-(1-甲基哌啶-4-基)苯基胺基]-5-酮基-8-苯基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-(3-氟苯基)-2-[2-甲氧基-4-哌啶-4-基苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-(4-氟苯基)-2-[2-甲氧基-4-哌啶-4-基苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[2-甲氧基-4-哌啶-4-基苯基胺基]-5-酮基-8-間甲苯基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[2-甲氧基-4-哌啶-4-基苯基胺基]-5-酮基-8-對甲苯基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-(3-甲氧基苯基)-2-(2-甲氧基-4-哌啶-4-基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[2-甲氧基-4-(2-吡咯啶-1-基乙基)苯基胺基]-5-酮基-8-苯基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-(4-氟苯基)-2-[2-甲氧基-4-(1-甲基哌啶-4-基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[2-甲氧基-4-(1-甲基哌啶-4-基)苯基胺基]-5-酮基-8-間甲苯基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-5-酮基-8-苯基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[4-(4-乙基哌嗪-1-基)-2-甲氧基苯基胺基]-5-酮基-8-苯基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；其呈鹼或酸加成鹽形式,以及呈水合物或溶劑合物形式。Among the compounds of the formula (I) which are the object of the present invention, the following compounds may be specifically mentioned in the order of the compounds of the following table: 7-amino-8-ethyl-2-(4-hydroxyphenylamino)- 5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-2-(benzothiazol-6-ylamino)-8-B 5--5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-2-[4-(cyclopropanecarbonylmethylamino)benzene Aminoamino]-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-ethyl-2- [4-(4-Methylpiperazine-1-carbonyl)phenylamino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; -amino-2-(4-cyclopentyloxyphenylamino)-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamidine Amine; 7-amino-8-ethyl-2-[4-(4-ethylpiperazin-1-yl)phenylamino]-5-keto-5,8-dihydropyrido[2 , 3-d] pyrimidine-6-formamide; 7-amino-8-ethyl-5-keto-2-[4-(4-pyrrolidin-1-ylpiperidin-1-yl)benzene Amino]-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-ethyl-5-keto-2-[4-(4 -pyrrolidin-1-ylpiperidin-1-yl)phenylamino]-5,8-dihydropyrido[2,3 -d]pyrimidine-6-formamide; 7-amino-8-ethyl-5-keto-2-[4-(4-pyrrolidin-1-ylpiperidin-1-yl)phenylamine -5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-cyclopentyl-2-(4-morpholin-4-ylphenyl Amino)-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-ethyl-5-keto-2- 4-(piperidin-1-sulfonyl)phenylamino]-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 2-[4-(4-B Mercaptopiperazin-1-yl)phenylamino]-7-amino-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6- Indoleamine; 7-amino-8-ethyl-2-(4-morpholin-4-ylbenzylamino)-5-one-5,8-dihydropyrido[2,3-d] Pyrimidine-6-formamide; 7-amino-8-ethyl-5-keto-2-(quinolin-3-ylamino)-5,8-dihydropyrido[2,3-d Pyrimidine-6-formamide; 7-amino-8-ethyl-5-keto-2-[4-(3-piperidin-1-ylpropoxy)phenylamino]-5, 8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl-5-keto-2-(3,4,5,6-tetrahydro- 2H-[1,2']bipyridin-5'-ylamino)-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-B 5-keto-2-[4-(2-ketopyrrolidin-1-yl)phenylamine ]-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl-5-one-2-(quinolin-6-ylamine) -5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl-2-(3-morpholin-4-ylphenylamine 5-)-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-2-(2,3-dihydrobenzo[1, 4] Dioxin-6-ylamino)-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-formamidine Amine; 7-amino-8-ethyl-2-(3-fluoro-4-hydroxyphenylamino)-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine- 6-carbamide; 7-amino-8-ethyl-2-(3-methylthiophenylamino)-5-keto-5,8-dihydropyrido[2,3-d Pyrimidine-6-formamide; 7-amino-8-ethyl-2-(4-morpholin-4-ylphenylamino)-5-keto-5,8-dihydropyridinium[ 2,3-d]pyrimidine-6-methanamine; 7-amino-8-ethyl-2-(4-morpholin-4-ylphenylamino)-5-keto-5,8- Dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl-2-(4-morpholin-4-ylphenylamino)-5-one -5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl-2-(2-fluorophenylamino)-5-one -5,8-dihydropyrido[2,3-d]pyrimidine-6- Indoleamine; 7-amino-2-[4-(4,4-difluoro[1,4']bipiperidin-1'-yl)-2-methoxyphenylamino]-8-B 5--5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide 7-amino-8-ethyl-2-[2-methoxy-4- (4-Trifluoromethyl[1,4']bipiperidin-1'-yl)phenylamino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine- 6-Protonamine 7-Amino-2-{4-[4-(3,3-difluoropyrrolidin-1-yl)piperidin-1-yl]-2-methoxyphenylamino} -8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide 7-amino-8-ethyl-2-[4-(4 -ethylpiperazin-1-yl)-2-fluoro-6-methoxyphenylamino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6- Formamide; 7-amino-2-[4-(1-cyclopropylpiperidin-4-yl)-2-methoxyphenylamino]-8-ethyl-5-one-5 , 8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-2-(2-dimethylaminomethyl) Alkan-6-ylamino)-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-2-[ 5-chloro-4-(4-cyclopropylpiperazin-1-yl)-2-methoxyphenylamino]-8-ethyl-5-keto-5,8-dihydropyridin[ 2,3-d]pyrimidine-6-formamide; 7-amino-8-ethyl-2-[2-methoxy-4-(4-morpholin-4-ylpiperidin-1-yl) Phenylamino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-2-[4-(4-cyclopropane) Piperazin-1-yl)-2-difluoromethoxyphenylamino]-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6 -carbamamine; 7-amino-2-[4-(4-cyclopropylpiperazin-1-yl)-2-methoxyphenylamino]-8-ethyl-5-one- 5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-ethyl-2-{2-methoxy-4-[1-(3, 3,3-trifluoropropyl)piperidin-4-yl]phenylamino}-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-Amino-2-[2-chloro-4-(4-ethylpiperazin-1-yl)phenylamino]-8-ethyl-5-keto-5,8-dihydropyridine [2,3-d]pyrimidine-6-formamide; 7-amino-8-ethyl-2-[4-(4-ethylpiperazin-1-yl)-3-trifluoromethylbenzene Amino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6- Indoleamine; 7-amino-8-ethyl-2-(4-morpholin-4-ylmethylphenylamino)-5-keto-5,8-dihydropyrido[2,3- d]pyrimidine-6-carbamide; 7-amino-8-ethyl-5-keto-2-{4-[4-(3,3,3-trifluoropropyl)piperazine-1- Phenylamino}-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-ethyl-2-[4-(4-ethyl Piperazin-1-yl)-3-fluorophenylamino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 6-(4 -morpholin-4-ylphenylamino)-9-keto-1,3,4,9-tetrahydro-2H-1,4a,5,7-tetraaza-phenanthrene-10-carboxamide 7-Amino-8-ethyl-2-[4-(4-ethylpiperazin-1-yl)-2-methoxyphenylamino]-5-one-5,8-di Hydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl-2-[4-(1-methylpiperidin-4-ylmethoxy)phenyl Amino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-2-[4-(4-cyclopropylpiperazine) -1-yl)phenylamino]-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8 -ethyl-2-[4-(4-ethylpiperazin-1-yl)-2-methylphenylamino]-5-keto-5,8-dihydropyrido[2,3- d]pyrimidine-6-formamide; 7-amino-8-ethyl-2-[4-(4-ethyl[1,4] Heterocyclic heptane-1-yl)phenylamino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 8-(4-morpholine) 4--4-Phenylamino)-5-keto-1,2,3,5-tetrahydro-3,7,9,9b-tetraaza-cyclopenta[cyclo]naphthalene-4 -carbamamine; 7-amino-8-ethyl-5-keto-2-{4-[2-(3-trifluoromethylpiperidin-1-yl)ethyl]phenylamino} -5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl-2-[4-(3-morpholin-4-ylpropyl) Phenylamino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl-5-keto- 2-{4-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]phenylamino}-5,8-dihydropyrido[2,3-d]pyrimidine- 6-carbamide; 7-amino-8-ethyl-2-(4-(S)-1-morpholin-3-ylmethylphenylamino)-5-keto-5,8- Dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-isobutyl-2-[4-(2-morpholin-4-ylethyl)phenylamine 5-yl-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl-2-{4-[2-( 3-fluoroazetidin-1-yl)ethyl]phenylamino}-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-Amino-2-[4-(2-morpholin-4-ylethyl)phenylamino]-5- Ketopropyl-8-propyl-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl-2-[4-(2-hydroxyl) Ethyl)phenylamino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl-2-( 4-hydroxyethylphenylamino)-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl-2 -(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-ylamino)-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine- 6-carbamide; 7-amino-2-{4-[2-(1,1-diketo-1λ6-thiomorpholin-4-yl)ethyl]phenylamino}-8-B 5--5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl-2-{4-[2-(4 -methyl-3-ketopiperazin-1-yl)ethyl]phenylamino}-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamidine Amine; 7-amino-8-ethyl-5-keto-2-{4-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]phenylamino}- 5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-ethyl-5-keto-2-{4-[1-(3,3 ,3-trifluoropropyl)piperidin-4-yl]phenylamino}-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-2 -(4-dimethylaminomethylphenylamino)-5-keto-8-(2,2,2-three Fluoroethyl)-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-2-[3-chloro-4-(4-pyrrolidine-1- Isopiperidin-1-yl)phenylamino]-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amine Benzyl-2-[3-chloro-4-(4-pyrrolidin-1-ylpiperidin-1-yl)phenylamino]-8-ethyl-5-keto-5,8-dihydropyridine And [2,3-d]pyrimidine-6-formamide; 7-amino-8-ethyl-5-keto-2-(4-pyridin-2-ylmethylphenylamino)-5 , 8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-2-{4-[2-(3,3-difluoropyrrolidin-1-yl) Phenylamino}-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl -5-keto-2-(4-pyrrolidin-3-ylphenylamino)-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino group -8-ethyl-5-keto-2-(4-pyrrolidin-3-ylphenylamino)-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide 7-Amino-8-ethyl-5-keto-2-[4-(2-piperidin-1-ylethyl)phenylamino]-5,8-dihydropyrido[2, 3-d]pyrimidin-6-formamide; 7-amino-2-[4-(2-morpholin-4-ylethyl)phenylamino]-5-keto-8-(2, 2,2-trifluoroethyl)-5,8-dihydropyrido[2,3-d] Pyridin-6-carbamide; 7-amino-2-{4-[2-(4,4-difluoropiperidin-1-yl)ethyl]phenylamino}-8-ethyl-5 -keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl-2-[4-(1-methylpyrrolidine- 3-yl)phenylamino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-2-{4-[2 -(3,3-difluoropiperidin-1-yl)ethyl]phenylamino}-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine -6-carbamamine; 7-amino-8-(3-methoxy-propyl)-2-[4-(2-morpholin-4-ylethyl)phenylamino]-5- Keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-ethyl-2-[4-(1-methylpiperidine-3 -yl)phenylamino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-2-(4-dimethyl Aminomethylphenylamino)-8-isopropyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-2 -(4-dimethylaminomethylphenylamino)-8-isopropyl-5-one-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide 7-Amino-8-ethyl-5-keto-2-(4-piperidin-3-ylphenylamino)-5,8-dihydropyrido[2,3-d]pyrimidine- 6-carbamide; 7-amino-8-ethyl-5-one -2-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7- Amino-8-ethyl-5-keto-2-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)-5,8-dihydropyrido[2,3- d]pyrimidine-6-formamide; 7-amino-8-ethyl-5-keto-2-(1,2,3,4-tetrahydroisoquinolin-6-ylamino)-5 , 8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl-2-[4-(1-methylpiperidin-4-yloxy) Phenylamino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl-2-[4- (2-morpholin-4-ylethoxy)phenylamino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amine Benzyl-2-(3-dimethylaminomethylphenylamino)-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6- Indoleamine; 7-amino-8-ethyl-5-keto-2-[4-(4-pyrrolidin-1-ylpiperidin-1-yl)phenylamino]-5,8-di Hydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl-5-keto-2-[4-(piperidin-4-yloxy)phenyl Amino]-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-(3-aminopropyl)-2-(4-morpholine -4-ylphenylamino)-5-keto-5,8-dihydropyrido[2,3-d] Pyrimidine-6-carbamide; 7-amino-8-ethyl-2-[4-(2-morpholin-4-ylethyl)phenylamino]-5-keto-5,8- Dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-2-(4-dimethylaminomethylphenylamino)-8-ethyl-5-one 5-,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl-2-[4-(1-ethylpiperidine-4- Phenylamino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-ethyl-5-one -2-(4-piperidin-4-ylphenylamino)-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-2-[3 -Chloro-4-(4-ethylpiperazin-1-yl)phenylamino]-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine- 6-carbamide; 7-amino-8-ethyl-2-[3-methoxy-4-(3-piperidin-1-ylpropoxy)phenylamino]-5-one -5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl-5-keto-2-{4-[2-(4- Trifluoromethylpiperidin-1-yl)ethyl]phenylamino}-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-2- {4-[2-(cis-2,6-dimethylmorpholin-4-yl)ethyl]phenylamino}-8-ethyl-5-one-5,8-dihydropyridine [2,3-d]pyrimidine-6-methanamine; 7-amino-2-(4- Diethylaminomethylphenylamino)-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino group -2-(4-Dimethylaminomethylphenylamino)-8-(3-methoxy-propyl)-5-one-5,8-dihydropyrido[2,3- d]pyrimidine-6-formamide; 7-amino-8-ethyl-2-[4-(4-ethylpiperazin-1-yl)-2-fluorophenylamino]-5-one 5-,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-2-{4-[1-(2-cyanoethyl)piperidine-4 -yl]phenylamino}-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-B 2-{4-[1-(3-fluoropropyl)piperidin-4-yl]phenylamino}-5-keto-5,8-dihydropyrido[2,3-d] Pyrimidin-6-carboxylic acid decylamine; 7-amino-8-ethyl-2-[4-(4-ethylpiperazin-1-yl)-3-methylphenylamino]-5-one -5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-2-[4-(4-cyclopropylpiperazin-1-yl)-2- Ethylphenylamino]-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; (±)-7-amino group- 2-trans-[4-(2-dimethylaminocyclopropyl)phenylamino]-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d] Pyrimidine-6-formamide; 7-amino-2-[4-(4-ring) Propyl piperazin-1-yl)-5-fluoro-2-methoxyphenylamino]-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d] Pyrimidine-6-formamide; 7-amino-2-[4-(4-cyclopropylpiperazin-1-yl)-3-fluoro-2-methoxyphenylamino]-8-B 5--5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-2-[4-(4-cyclopropylpiperazine-1 -yl)-2-ethoxyphenylamino]-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7- Amino-8-ethyl-5-keto-2-(4-propylphenylamino)-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; -amino-8-ethyl-5-keto-2-(4-propoxyphenylamino)-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide 7-Amino-8-ethyl-2-(6-methoxypyridin-3-ylamino)-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine- 6-carbamide; 7-amino-8-ethyl-2-(4-fluorophenylamino)-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine- 6-carbamide; 7-amino-8-ethyl-2-(4-methoxyphenylamino)-5-one-5,8-dihydropyrido[2,3-d] Pyrimidine-6-formamide; 7-amino-2-(benzo[1,3]dioxol-5-ylamino)-8-ethyl-5-keto-5,8 -dihydropyrido[2,3-d]pyrimidine-6-A Indoleamine; 7-amino-8-ethyl-5-keto-2-(4-piperidin-1-ylphenylamino)-5,8-dihydropyrido[2,3-d] Pyrimidine-6-carbamide; 8-ethyl-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]phenylamino }-7-Methylamino-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-Amino-8-isobutyl-2- {2-Methoxy-4-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]phenylamino}-5-keto-5,8-dihydropyridine [2,3-d]pyrimidine-6-formamide; 7-amino-8-cyclopropylmethyl-2-{2-methoxy-4-[1-(3,3,3-three Fluoropropyl)piperidin-4-yl]phenylamino}-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino group- 8-(2-Methoxyethyl)-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]phenylamino} -5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-2-{2-methoxy-4-[1-(3 ,3,3-trifluoropropyl)piperidin-4-yl]phenylamino}-5-keto-8-(tetrahydrofuran-2-ylmethyl)-5,8-dihydropyrido[2 , 3-d] pyrimidine-6-formamide; 7-amino-8-ethyl-5-keto-2-{4-[1-(3,3,3-trifluoropropyl)aza Cyclobutane-3-yl]phenylamino}-5,8-dihydropyrido[2,3-d]pyrimidin-6-A Amine; 7-amino-2-{5-fluoro-2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]phenylamino}- 8-isobutyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl-5-keto-2 -[4-(1,2,3,6-tetrahydropyridin-4-yl)phenylamino]-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-Amino-2-(2-methoxy-4-piperidin-4-ylphenylamino)-5-keto-8-phenyl-5,8-dihydropyrido[2,3 -d]pyrimidine-6-carbamide; 7-amino-8-(2-hydroxyethyl)-2-(2-methoxy-4-piperidin-4-ylphenylamino)-5 -keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-2-{2-methoxy-4-[1-(3,3 ,3-trifluoropropyl)piperidin-4-yl]phenylamino}-5-keto-8-thiazol-2-ylmethyl-5,8-dihydropyrido[2,3-d Pyrimidine-6-formamide; 7-amino-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]phenylamine }-5-keto-8-thiazol-5-ylmethyl-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-(2 -hydroxy-2-methylpropyl)-2-(2-methoxy-4-piperidin-4-ylphenylamino)-5-keto-5,8-dihydropyrido[2, 3-d]pyrimidin-6-formamide; 8-(2-acetamidoethyl)-7-amine -2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]phenylamino}-5-keto-5,8-di Hydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-(2-aminoethyl)-2-(4-morpholin-4-ylphenylamino) -5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-2-(4-morpholin-4-ylphenylamino) -5-keto-8-pyrrolidin-3-ylmethyl-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-ethyl- 2-[4-(4-Ethylpiperazin-1-yl)-2-hydroxyphenylamino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6 -carbamamine; 7-amino-2-(4-morpholin-4-ylphenylamino)-5-keto-8-piperidin-4-ylmethyl-5,8-dihydropyridine And [2,3-d]pyrimidine-6-methanamine; 7-amino-2-(2-methoxy-4-morpholin-4-ylphenylamino)-5-one-8 -pyrrolidin-3-ylmethyl-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-ethyl-2-(2-methoxy 4--4-piperidin-4-ylphenylamino)-4-methyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; -amino-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]phenylamino}-5-oneyl-8- Thiophen-2-ylmethyl-5,8-dihydropyrido[2,3-d]pyrimidine-6- Formamide; 7-amino-8-isobutyl-2-[2-methoxy-4-(4-morpholin-4-ylpiperidin-1-yl)phenylamino]-5- Keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-2-(4-morpholin-4-ylphenylamino)-5- Keto-8-pyrrolidin-2-ylmethyl-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-ethyl-2-{ 2-methoxy-4-[1-(3,3,3-trifluoropropyl)-1,2,3,6-tetrahydropyridin-4-yl]phenylamino}-5-one -5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-2-[4-(4-ethylpiperazin-1-yl)-2-methyl Oxyphenylamino]-8-(2-hydroxy-2-methylpropyl)-5-one-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide 7-Amino-8-(2-hydroxy-2-methylpropyl)-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperidine- 4-yl]phenylamino}-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-(2-hydroxy- 2-methylpropyl)-2-[4-(4-ethylpiperidin-1-yl)-2-methoxyphenylamino]-5-one-5-8-dihydropyridine [2,3-d]pyrimidine-6-carboxamide; 7-amino-2-[4-(1-cyclopropylpiperidin-4-yl)-2-methoxyphenylamino]- 8-(2-hydroxy-2-methylpropyl)-5-keto-5,8-dihydropyrido[2, 3-d]pyrimidine-6-carbamide; 7-amino-8-(2-hydroxy-2-methylpropyl)-2-{2-methoxy-4-[1-(2-A Oxyethyl)piperidin-4-yl]phenylamino}-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino group -2-[2-methoxy-4-(1-methylpiperidin-4-yl)phenylamino]-5-keto-8-phenyl-5,8-dihydropyrido[2 , 3-d] pyrimidine-6-formamide; 7-amino-8-(3-fluorophenyl)-2-[2-methoxy-4-piperidin-4-ylphenylamino] -5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-(4-fluorophenyl)-2-[2- Oxy-4-piperidin-4-ylphenylamino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino group- 2-[2-Methoxy-4-piperidin-4-ylphenylamino]-5-keto-8-m-tolyl-5,8-dihydropyrido[2,3-d]pyrimidine -6-carbamamine; 7-amino-2-[2-methoxy-4-piperidin-4-ylphenylamino]-5-keto-8-p-tolyl-5,8- Dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-(3-methoxyphenyl)-2-(2-methoxy-4-piperidine- 4-ylphenylamino)-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-2-[2-methoxy -4-(2-pyrrolidin-1-ylethyl)phenylamino]- 5-keto-8-phenyl-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-(4-fluorophenyl)-2- [2-Methoxy-4-(1-methylpiperidin-4-yl)phenylamino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6 -carbamamine; 7-amino-2-[2-methoxy-4-(1-methylpiperidin-4-yl)phenylamino]-5-keto-8-m-tolyl- 5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-2-{2-methoxy-4-[1-(3,3,3-three Fluoropropyl)piperidin-4-yl]phenylamino}-5-keto-8-phenyl-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-Amino-2-[4-(4-ethylpiperazin-1-yl)-2-methoxyphenylamino]-5-keto-8-phenyl-5,8-dihydro Pyrido[2,3-d]pyrimidin-6-carboxamide; in the form of a base or acid addition salt, and in the form of a hydrate or solvate.

本發明化合物之群之組合亦作為一實施例構成本發明之一部分。Combinations of the groups of compounds of the invention also form an embodiment of the invention as an embodiment.

根據本發明，通式(I)之化合物可根據以下方法來製備。According to the present invention, the compound of the formula (I) can be produced according to the following method.

根據第一實施例，本發明方法包括用式(A)之一級胺來親核取代式(IX)之化合物的步驟：According to a first embodiment, the process of the invention comprises the step of nucleophilically replacing a compound of formula (IX) with a monoamine of formula (A):

其中R1 、R2 、R3 、R4 及R5 如通式(I)中所定義。此方法可形成式(I)化合物，尤其為式(I")化合物。Wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined in the formula (I). This process can form compounds of formula (I), especially compounds of formula (I").

根據以下流程1，依據由D. Boschelli等人，J. Med. Chem .(1998),41,4365-4377所述之方法，使4-氯-2-甲基硫吡啶-5-甲酸乙酯(II，其中A=CH)(根據Todd等人，J. Amer. Chem. Soc .(1943),65,350-354；Pesson,M.,Eur. J. Med. Chem .(1974),9(6),585-590；Shadbolt,R.,J. Chem. soc .(1967),13,1172-1178來製備)或4-氯-6-甲基-2-甲基硫吡啶-5-甲酸乙酯(II，其中A=C-Me)(根據WO 2005/105801中所述之方法來製備)與式R5 -NH2 之胺(其中R5 如上文關於本發明之式(I)所定義)在諸如THF或二噁烷之有機溶劑中且在有機鹼(例如三乙胺)存在下，在室溫下反應，得到式(III)之4-胺基-2-甲基硫吡啶-5-甲酸乙酯衍生物。According to the following Scheme 1, ethyl 4-chloro-2-methylthiopyridine-5-carboxylate was obtained according to the method described by D. Boschelli et al., J. Med. Chem . (1998), 41, 4365-4377. (II, where A = CH) (according to Todd et al, J. Amer. Chem. Soc . (1943), 65, 350-354; Pesson, M., Eur. J. Med. Chem . (1974), 9 (6) ), 585-590; Shadbolt, R., J. Chem. soc . (1967), 13, 1172-1178) or 4-chloro-6-methyl-2-methylthiopyridine-5-formate B Esters (II, wherein A = C-Me) (prepared according to the method described in WO 2005/105801) and amines of the formula R 5 -NH 2 (wherein R 5 is as defined above for the formula (I) of the invention It is reacted in an organic solvent such as THF or dioxane in the presence of an organic base such as triethylamine at room temperature to give 4-amino-2-methylthiopyridine-5 of formula (III) - ethyl formate derivative.

接著在介於20℃與100℃之間的溫度下以氫氧化鈉或氫氧化鉀或氫氧化鋰水解式(III)之4-胺基嘧啶衍生物之酯基，得到相應的式(IV)之羧酸。接著經由熟習此項技術者已知之方法活化羧酸基團，諸如使用亞硫醯氯將羧酸基團轉化為酸氯化物，或宜藉由使其與過量三聚氟化氰(C3 N3 F3 )在諸如二氯甲烷之惰性溶劑中，在諸如吡啶或宜為三乙胺之有機鹼存在下反應而將其轉化為式(V)之酸氟化物。關於此反應之更多細節，可參看Synthesis 1973,487。Then, the ester group of the 4-aminopyrimidine derivative of the formula (III) is hydrolyzed with sodium hydroxide or potassium hydroxide or lithium hydroxide at a temperature between 20 ° C and 100 ° C to obtain the corresponding formula (IV). Carboxylic acid. Followed by those skilled in the art by methods known in the activated carboxylic acid group, such as acyl chloride using thionyl the carboxylic acid group is converted to an acid chloride, or reacted with an excess should by cyanuric fluoride (C 3 N 3 F 3 ) is converted to the acid fluoride of formula (V) by reaction in the presence of an organic base such as pyridine or triethylamine in an inert solvent such as dichloromethane. See Synthesis 1973, 487 for more details on this reaction.

使由此所獲的式(V)之酸氟化物與式(VI)之氰基乙醯胺在諸如氫化鈉(NaH)之強鹼存在下，在極性溶劑(宜為DMF)中，在常溫下縮合。若添加2當量NaH，則可獲得式(VII)之β-酮基氰基乙醯胺，藉由在諸如DMF、DMSO或正丁醇之極性溶劑中在100℃以上之溫度下加熱將其環化成式(VIII)之吡啶并[2,3-d]嘧啶衍生物。另一方面，若在第一階段中在2當量氫化鈉存在下，使式(V)之酸氟化物與式(VI)之氰基乙醯胺接觸且接著在當場形成β-酮基氰基乙醯胺之後添加第三當量，則將式(V)之化合物直接環化成式(VIII)之吡啶并[2,3-d]嘧啶衍生物。接著如例如由D.Boschelli等人，J.Med. Chem. (1998),41,4365-4377及以編號WO 96/34867所公開之國際PCT專利申請案中所述，藉由與諸如間過氯苯甲酸、過氧化氫、過硼酸鈉及硫酸氫鉀或反-2-苯磺醯基-3-苯基噁吖丙啶之氧化劑反應將式(VIII)之化合物之甲基硫基氧化(在流程1中為[Ox]符號)為相應的亞碸(n=1)與碸(n=2)衍生物。使式(IX)之碸與亞碸混合物與一級胺在諸如DMF、DMSO或NMP之極性溶劑中，在介於75℃與150℃之間的溫度下經由芳族親核取代反應，得到式(I")之化合物，其為作為本發明之目標的式(I)化合物之子群，其中A表示-CH=且R6 表示氫原子。應瞭解，在流程1中所述之方法中，基團R1 、R2 、R3 、R4 或R5 可包含一或多個臨時保護基。The thus obtained acid fluoride of the formula (V) and the cyanoacetamide of the formula (VI) are present in a polar solvent (preferably DMF) in the presence of a strong base such as sodium hydride (NaH) at room temperature. Lower condensation. If 2 equivalents of NaH are added, β-ketocyanoacetamide of the formula (VII) can be obtained by heating it in a polar solvent such as DMF, DMSO or n-butanol at a temperature above 100 ° C. A pyrido[2,3-d]pyrimidine derivative of the formula (VIII) is obtained. On the other hand, if in the first stage, in the presence of 2 equivalents of sodium hydride, the acid fluoride of formula (V) is contacted with cyanoacetamide of formula (VI) and then the β-ketocyano group is formed on the spot. After the third equivalent of acetamide is added, the compound of formula (V) is directly cyclized to the pyrido[2,3-d]pyrimidine derivative of formula (VIII). And as described, for example, by D. Boschelli et al., J. Med. Chem. (1998), 41, 4365-4377, and the International PCT Patent Application No. WO 96/34867, by Oxidation reaction of chlorobenzoic acid, hydrogen peroxide, sodium perborate and potassium hydrogensulfate or trans-2-benzenesulfonyl-3-phenyloxanyl chloride oxidizes the methylthio group of the compound of formula (VIII) ( The [Ox] symbol in Scheme 1 is the corresponding derivative of 碸 (n=1) and 碸(n=2). The hydrazine nucleophilic substitution reaction between the hydrazine of the formula (IX) and the hydrazine mixture and the primary amine in a polar solvent such as DMF, DMSO or NMP at a temperature between 75 ° C and 150 ° C gives the formula ( a compound of I") which is a subgroup of the compound of formula (I) which is the object of the present invention, wherein A represents -CH= and R 6 represents a hydrogen atom. It is to be understood that in the method described in Scheme 1, a group R 1 , R 2 , R 3 , R 4 or R 5 may contain one or more temporary protecting groups.

根據另一實施例，本發明方法包括使通式(XIV)或(XV)之化合物According to another embodiment, the process of the invention comprises the compound of formula (XIV) or (XV)

與通式(A)之化合物Compound with formula (A)

(其中R1 、R2 、R3 、R4 、R5 及R6 如通式(I)中所定義)經由親核取代反應或由鈀複合物催化的布赫瓦爾德/哈特維希(Bchwald/Hartwig)型偶合反應進行反應之步驟。此方法可形成式(I)化合物，尤其式(I")及(I''')之化合物。(wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in formula (I)) via nucleophilic substitution reaction or Buchwald/Hartwig catalyzed by a palladium complex (B The chwald/Hartwig type coupling reaction carries out the reaction step. This process can form compounds of formula (I), especially compounds of formula (I") and (I''').

根據流程2，依據V.H. Smith及B.E. Christensen(J. Am. Chem. Soc. 1955,20,829)之方法，使尿嘧啶-5-甲酸(X)與***在N,N-二乙苯胺存在下反應，得到2,4-二氯-5-嘧啶甲酸(XI)。宜可能直接使用商用2,4-二氯-5-嘧啶甲酸氯化物，對其進行受控水解。在室溫下，在諸如THF或二噁烷之有機溶劑中且在例如三乙胺之有機鹼存在下，以式R5 -NH2 之胺(其中R5 如上文關於本發明之式(I)所定義)選擇性取代中間物(XI)之4位置上的氯原子，得到式(XII)之4-胺基-2-氯嘧啶-5-甲酸衍生物。隨後經由熟習此項技術者已知之方法活化羧酸基團，諸如使用亞硫醯氯將羧酸基團轉化為酸氯化物，或宜藉由將其與過量三聚氟化氰在諸如二氯甲烷之惰性溶劑中，在諸如三乙胺之有機鹼存在下反應而將其轉化為式(XIII)之酸氟化物。According to Scheme 2, uracil-5-formic acid (X) and phosphorus oxychloride are present in N,N-diethylaniline according to the method of VH Smith and BE Christensen (J. Am. Chem. Soc. 1955, 20, 829). The reaction was carried out to obtain 2,4-dichloro-5-pyrimidinecarboxylic acid (XI). Commercially available 2,4-dichloro-5-pyrimidinecarboxylic acid chloride may be used directly for controlled hydrolysis. An amine of the formula R 5 —NH 2 (wherein R 5 is as defined above for the invention (I) in the presence of an organic solvent such as THF or dioxane and in the presence of an organic base such as triethylamine ) is defined as the selective replacement of the chlorine atom at the 4-position of the intermediate (XI) to give a 4-amino-2-chloropyrimidine-5-carboxylic acid derivative of the formula (XII). The carboxylic acid group is then activated by methods known to those skilled in the art, such as the conversion of a carboxylic acid group to an acid chloride using sulfinium chloride, or preferably by intercalating it with an excess of cyanuric chloride, such as dichloro In an inert solvent of methane, it is converted into an acid fluoride of the formula (XIII) by reacting in the presence of an organic base such as triethylamine.

使由此所獲的式(XIII)之酸氟化物與式(VI)之氰基乙醯胺在常溫下，在諸如氫化鈉(NaH)之過量強鹼存在下，在宜為DMF之極性溶劑中縮合。在2當量氫化鈉存在下且接著在當場形成β-酮基氰基乙醯胺之後添加第三當量，將式(XIII)之化合物在常溫下直接轉化為式(XIV)之吡啶并[2,3-d]嘧啶衍生物。可使氯基中間物(XIV)直接與一級胺或二級胺藉由芳族親核取代或藉由以諸如鈀之金屬催化的布赫瓦爾德/哈特維希偶合，在介於75℃與150℃之間的溫度下，視情況在微波機器中反應，得到式(I")之化合物，其為作為本發明之目標的式(I)化合物之子群，其中R6 表示氫原子且A表示-CH=。可在諸如氫化鈉或第三丁醇鉀之鹼及烷化劑(宜為烷基碘)存在下，在諸如DMF之極性溶劑中將氯基中間物(XIV)預先在環外胺基上烷基化而得到(XV)，以最終得到式(I''')之化合物，其為作為本發明之目標的式(I)化合物之子群，其中R6 ≠H且如上所定義且A表示-CH=。應瞭解在流程2中所述之方法中，基團R1 、R2 、R3 、R4 、R5 或R6 可包含一或多個臨時保護基。The thus obtained acid fluoride of the formula (XIII) and the cyanoacetamide of the formula (VI) are present in a polar solvent of DMF at room temperature in the presence of an excess of a strong base such as sodium hydride (NaH). Condensation. The compound of formula (XIII) is directly converted to the pyridine of formula (XIV) at room temperature in the presence of 2 equivalents of sodium hydride and then after the formation of β-ketocyanoacetamide in the presence of a third equivalent. 3-d] pyrimidine derivatives. The chlorine-based intermediate (XIV) can be directly substituted with a primary or secondary amine by aromatic nucleophilic substitution or by Buchwald/Hartwig coupling catalyzed by a metal such as palladium at 75 ° C Reaction with a microwave machine, at a temperature between 150 ° C and the like, to give a compound of the formula (I") which is a subgroup of the compound of the formula (I) which is the object of the present invention, wherein R 6 represents a hydrogen atom and A Represents -CH=. The chlorine-based intermediate (XIV) can be pre-in the ring in a polar solvent such as DMF in the presence of a base such as sodium hydride or potassium butoxide and an alkylating agent (preferably an alkyl iodide). Alkylation of the exoamine group to give (XV) to give the compound of formula (I''') which is a subgroup of the compound of formula (I) which is the object of the present invention, wherein R 6 ≠H and as above Definitions and A represents -CH=. It will be appreciated that in the process described in Scheme 2, the group R 1 , R 2 , R 3 , R 4 , R 5 or R 6 may comprise one or more temporary protecting groups.

在流程1及2中，當未描述起始化合物及試劑之製備方法時，其可購得或如文獻中所述，或者可根據其中所述或熟習此項技術者已知之方法來製備。In Schemes 1 and 2, when the methods of preparation of the starting compounds and reagents are not described, they are commercially available or as described in the literature, or may be prepared according to methods known to those skilled in the art.

根據其另一態樣，本發明之目標亦為式(VII)、(VIII)、(IX)及(XV)之化合物，其中R6 不為氫原子，該等化合物係如合成流程1及2中定義。此等化合物適用作式(I)化合物之合成中間物。According to another aspect thereof, the object of the present invention is also a compound of the formula (VII), (VIII), (IX) and (XV) wherein R 6 is not a hydrogen atom, and the compounds are as in Synthetic Schemes 1 and 2 Defined in . These compounds are suitable as synthetic intermediates for the compounds of formula (I).

以下實例描述某些本發明化合物之製備。此等實例不具限制性且僅用以說明本發明。以實例形式呈現的化合物之編號係指下表中給出之彼等編號，其說明許多本發明化合物之化學結構及物理性質。The following examples describe the preparation of certain compounds of the invention. These examples are not limiting and are merely illustrative of the invention. The numbering of the compounds presented by way of example refers to the numbers given in the table below, which illustrate the chemical structures and physical properties of many of the compounds of the invention.

使用以下縮寫及實驗式：Use the following abbreviations and experimental formulas:

CH2 Cl2 　二氯甲烷CH 2 Cl 2 dichloromethane

HPLC　高效液相層析HPLC high performance liquid chromatography

LC/MS　液相層析/質譜分析LC/MS liquid chromatography/mass spectrometry

d　雙重峰d double peak

DMF　二甲基甲醯胺DMF dimethylformamide

DMSO　二甲亞碸DMSO dimethyl hydrazine

dppf　二苯基膦基二茂鐵Dppf diphenylphosphinoferrocene

Et3 N　三乙胺Et 3 N triethylamine

h　小時h hours

HCl　鹽酸HCl hydrochloric acid

MHz　百萬赫茲MHz million hertz

m　多重峰或未解析之複雜物m multiple peaks or unresolved complexes

min　分鐘Min minute

MeOH　甲醇MeOH methanol

MgSO4 　硫酸鎂MgSO 4 magnesium sulfate

NaCl　氯化鈉NaCl sodium chloride

NaHCO3 　碳酸氫鈉NaHCO 3 sodium bicarbonate

NaOH　氫氧化鈉NaOH sodium hydroxide

Na2 SO4 　硫酸鈉Na 2 SO 4 sodium sulfate

NH4 Cl　氯化銨NH 4 Cl ammonium chloride

NH4 OH　氫氧化銨NH 4 OH ammonium hydroxide

NMP　N -甲基吡咯啶酮NMP N -methylpyrrolidone

ppm　百萬分率Ppm parts per million

s　單峰s single peak

t　三重峰t triplet

THF　四氫呋喃THF tetrahydrofuran

實例1：7-胺基-8-乙基-2-[(4-羥基苯基)胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺Example 1: 7-Amino-8-ethyl-2-[(4-hydroxyphenyl)amino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6 -Procarbamide

1.1：4-乙基胺基-2-甲硫基-5-嘧啶甲酸乙酯1.1: Ethyl 4-ethylamino-2-methylthio-5-pyrimidinecarboxylate

向15.0 g(64.0 mmol)4-氯-2-甲硫基-5-嘧啶甲酸乙酯及195 mL(1.39 mol)三乙胺於226 mL THF中之溶液中添加14.6 mL 70%乙胺水溶液。在室溫下攪拌混合物2小時。於水中稀釋之後，以乙酸乙酯萃取所得混合物且經MgSO4 乾燥有機相。藉由矽膠層析，以環己烷/EtOAc混合物(8/15)溶離來純化產物。獲得13.7 g呈無色油狀之預期產物。產率=89%。To a solution of 15.0 g (64.0 mmol) of ethyl 4-chloro-2-methylthio-5-pyrimidinecarboxylate and 195 mL (1.39 mol) of triethylamine in 226 mL of THF was added 14.4 mL of a 70% aqueous solution of ethylamine. The mixture was stirred at room temperature for 2 hours. After dilution in water to the resulting mixture was extracted with ethyl acetate and the organic phase was dried over MgSO 4. The product was purified by silica gel chromatography eluting with a cyclohexane/EtOAc mixture (8/15). 13.7 g of the expected product was obtained as a colorless oil. Yield = 89%.

1.2：4-乙基胺基-2-甲硫基5-嘧啶甲酸1.2: 4-ethylamino-2-methylthio 5-pyrimidinecarboxylic acid

將含有6.33 g(26.0 mmol)4-乙基胺基-2-甲硫基-5-嘧啶甲酸乙酯、65 mL(65.0 mmol)1 N NaOH及60 mL乙醇之混合物回流1小時。在減壓下蒸發掉乙醇且將殘餘物於100 mL水中稀釋。添加65 mL 1 N HCl水溶液且藉由抽吸排乾所形成之白色沈澱物。以水沖洗固體且在真空下乾燥。獲得5.1 g呈白色固體狀之預期產物。熔點=188℃。產率=92%。A mixture containing 6.33 g (26.0 mmol) of ethyl 4-ethylamino-2-methylthio-5-pyrimidinecarboxylate, 65 mL (65.0 mmol) 1 N NaOH and 60 mL of ethanol was refluxed for one hour. Ethanol was evaporated under reduced pressure and the residue was diluted in 100 mL water. A white precipitate of 65 mL of 1 N aqueous HCl was added and drained by suction. The solid was rinsed with water and dried under vacuum. 5.1 g of the expected product was obtained as a white solid. Melting point = 188 °C. Yield = 92%.

1.3：4-乙基胺基-2-甲硫基-5-嘧啶甲酸氟化物1.3: 4-ethylamino-2-methylthio-5-pyrimidinecarboxylic acid fluoride

向含有3.0 g(14.0 mmol)4-乙基胺基-2-甲硫基-5-嘧啶甲酸及2.1 mL(15.0 mmol)三乙胺於50 mL CH2 Cl2 中之溶液中添加2.3 mL(28.0 mmol)三聚氟化氰。攪拌混合物3小時且以250 mL CH2 Cl2 及75 mL冰冷水稀釋溶液。在藉由沈降分離各相之後，以75 mL冰冷水洗滌有機相且經MgSO4 乾燥。隨後在減壓下蒸發掉溶劑。獲得3.0 g呈綠色膠狀之預期產物。產率係定量的。Add 2.3 mL to a solution containing 3.0 g (14.0 mmol) of 4-ethylamino-2-methylthio-5-pyrimidinecarboxylic acid and 2.1 mL (15.0 mmol) of triethylamine in 50 mL of CH 2 Cl 2 ( 28.0 mmol) cyanuric chloride. The mixture was stirred for 3 hours and the solution was diluted with 250 mL CH 2 Cl 2 and 75 mL ice cold water. After separating the phases by sedimentation, the organic phase was washed with 75 mL of ice cold water and dried over MgSO 4 . The solvent was then evaporated under reduced pressure. 3.0 g of the expected product was obtained as a green gum. The yield is quantitative.

1.4：7-胺基-8-乙基-2-(甲硫基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-甲醯胺1.4:7-Amino-8-ethyl-2-(methylthio)-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-carboxamide

向已冷卻至0℃至5℃的1.18 g(14.0 mmol)氰基乙醯胺於20 mL無水DMF中之溶液中添加1.12 g(28 mmol)60% NaH。添加之後，在室溫下攪拌混合物10分鐘且隨後再次在冰水浴中冷卻，且添加步驟1.3中所製備之酸氟化物(14.0 mmol)在30 mL無水DMF中的溶液。在室溫下攪拌反應混合物30分鐘，且添加0.56 g(14.0 mmol)60% NaH。在室溫下攪拌混合物1小時，且隨後添加100 mL水。藉由過濾分離出沈澱物，以水沖洗，藉由抽吸排乾且隨後在烘箱中乾燥。獲得2.85 g呈黃色固體狀之預期產物。產率=73%。To a solution of 1.18 g (14.0 mmol) of cyanoacetamide in 20 mL of dry DMF cooled to 0 ° C to 5 ° C was added 1.12 g (28 mmol) of 60% NaH. After the addition, the mixture was stirred at room temperature for 10 minutes and then cooled again in an ice water bath, and a solution of the acid fluoride (14.0 mmol) prepared in the step 1.3 in 30 mL of anhydrous DMF was added. The reaction mixture was stirred at room temperature for 30 minutes and 0.56 g (14.0 mmol) of 60% NaH was added. The mixture was stirred at room temperature for 1 hour, and then 100 mL of water was added. The precipitate was separated by filtration, rinsed with water, drained by suction and then dried in an oven. 2.85 g of the expected product are obtained as a yellow solid. Yield = 73%.

1.5：7-胺基-8-乙基-2-(甲基磺醯基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺1.5:7-Amino-8-ethyl-2-(methylsulfonyl)-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide

向0.60 g(2.15 mmol)在步驟1.4中獲得的化合物於20 mL N-甲基吡咯啶酮中之溶液中添加1.08 g(4.83 mmol)間氯過苯甲酸。在室溫下攪拌混合物24小時且隨後蒸發至乾燥。將固體殘餘物溶解於NaHCO3 水溶液中且隨後濾出。藉由抽吸排乾固體且隨後在烘箱中乾燥。獲得0.4 g呈淡黃色固體狀之預期產物。產率=60%.To a solution of 0.60 g (2.15 mmol) of the compound obtained in step 1.4 in 20 mL of N-methylpyrrolidone was added 1.08 g (4.83 mmol) of m-chloroperbenzoic acid. The mixture was stirred at room temperature for 24 hours and then evaporated to dryness. The solid residue was dissolved in aqueous NaHCO 3 solution and then filtered off. The solids were drained by suction and then dried in an oven. Obtained 0.4 g of the expected product as a pale yellow solid. Yield = 60%.

1.6：7-胺基-8-乙基-2-[(4-羥基苯基)胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺1.6:7-Amino-8-ethyl-2-[(4-hydroxyphenyl)amino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6- Formamide

向0.40 g(1.29 mmol)於步驟1.5中獲得的產物於4 mL無水DMSO中之溶液中添加0.160 g(1.47 mmol)4-胺基苯酚。在110℃下加熱反應混合物隔夜且隨後蒸發至乾燥。藉由矽膠層析，以二氯甲烷/甲醇梯度(100/0至90/10)溶離來純化固體殘餘物。獲得0.090 g呈灰白色固體狀之預期產物。產率=20%。m.p.>260℃。M+H+= 341。To a solution of 0.40 g (1.29 mmol) of the product obtained in step 1.5 in 4 mL of anhydrous DMSO was added 0.160 g (1.47 mmol) of 4-aminophenol. The reaction mixture was heated at 110 ° C overnight and then evaporated to dryness. The solid residue was purified by silica gel chromatography eluting with dichloromethane/methanol gradient (100/0 to 90/10). Obtained 0.090 g of the desired product as a white solid. Yield = 20%. Mp>260 °C. M+H += 341.

1 H NMR(DMSO-d6;400 MHz):δ11.70(寬s,1H);9.85(s,1H);8.89(s,1H);7.95(寬s,1H);7.48(d,2H);7.72(d,2H);4.29(q,2H);1.20(t,3H)。 1 H NMR (DMSO-d6; 400 MHz): δ 11.70 (width s, 1H); 9.85 (s, 1H); 8.89 (s, 1H); 7.95 (width s, 1H); 7.48 (d, 2H) ; 7.72 (d, 2H); 4.29 (q, 2H); 1.20 (t, 3H).

實例2：7-胺基-8-乙基-2-[4-(4-甲基哌嗪-1-羰基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺Example 2: 7-Amino-8-ethyl-2-[4-(4-methylpiperazine-1-carbonyl)phenylamino]-5-one-5-8-dihydropyridinium [ 2,3-d]pyrimidine-6-formamide

2.1(4-甲基哌嗪-1-基)(4-硝基苯基)甲酮2.1(4-Methylpiperazin-1-yl)(4-nitrophenyl)methanone

將2.0 g 4-硝基苯甲酸(11.97 mmol)、10.42 mL二異丙基乙胺(59.84 mmol)及1.46 mL 1-甲基哌嗪(13.16 mmol)於40 mL DMF中之混合物在冰浴上冷卻至2-5℃。隨後逐份添加11.53 g(35.9 mmol)四氟硼酸O-苯并***基四甲基異(TBTU，CAS編號=125700-67-6)且在室溫下攪拌混合物隔夜。以二氯甲烷及NaCl飽和水溶液稀釋反應混合物。在藉由沈降分離各相之後，以二氯甲烷萃取水相。合併有機相，經Na2 SO4 乾燥，過濾且在真空下濃縮。藉由抽吸排乾含有不溶性物質之油性殘餘物且接著以二氯甲烷及少量甲醇沖洗。獲得1.67g呈淡粉色固體狀之預期產物，其在未進一步純化之情況下按原樣使用。產率=56%。A mixture of 2.0 g of 4-nitrobenzoic acid (11.97 mmol), 10.42 mL of diisopropylethylamine (59.84 mmol) and 1.46 mL of 1-methylpiperazine (13.16 mmol) in 40 mL of DMF on ice bath Cool to 2-5 ° C. Subsequently, 11.53 g (35.9 mmol) of O-benzotriazolyl tetramethyltetrafluoroborate was added in portions. (TBTU, CAS number = 125700-67-6) and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with a saturated aqueous solution of dichloromethane and NaCl. After separating the phases by sedimentation, the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over Na 2 SO 4, filtered and concentrated in vacuo. The oily residue containing the insoluble material was drained by suction and then rinsed with dichloromethane and a small amount of methanol. The expected product was obtained as a pale pink solid, which was used as it was without further purification. Yield = 56%.

2.2：(4-胺基苯基)(4-甲基哌嗪-1-基)甲酮2.2: (4-Aminophenyl)(4-methylpiperazin-1-yl)methanone

在惰性氛圍下向部分溶解於50 mL甲醇中的1.67 g(6.70 mmol)在步驟2.1中製備的產物中添加71 mg 10%鈀/木炭。在室溫下，在3巴氫氣下攪拌反應混合物2小時30分鐘且隨後經由矽藻土過濾。在蒸發至乾燥之後，獲得1.5 g呈橙色油狀之預期產物，其按原樣用於下一步中。定量產率。To a product prepared in step 2.1, 1.67 g (6.70 mmol) partially dissolved in 50 mL of methanol was added 71 mg of 10% palladium/ charcoal under an inert atmosphere. The reaction mixture was stirred under 3 bar of hydrogen for 2 hours and 30 minutes at room temperature and then filtered through Celite. After evaporation to dryness, 1.5 g of the desired product was obtained as an orange oil, which was used in the next step. Quantitative yield.

2.3：2,4-二氯-5-嘧啶甲酸2.3: 2,4-dichloro-5-pyrimidinecarboxylic acid

-方法A：- Method A:

在低溫條件下向部分溶解於20 mL DMF中的10.0 g(64.06 mmol)尿嘧啶-5-甲酸(Aldrich Chemical Company)中添加59.7 mL(0.64 mol)***及10.3 mL(64.7 mmol)N,N -二乙基苯胺，且隨後在90℃下加熱混合物2小時40分鐘。在冷卻至室溫且蒸發掉一半過量的POCl3 之後，將介質傾入冰中且隨後以***萃取。合併***相，經硫酸鈉乾燥，過濾且在真空下濃縮。以65%產率獲得8.1 g(41.97 mmol)2,4-二氯-5-嘧啶甲酸。59.7 mL (0.64 mol) of phosphorus oxychloride and 10.3 mL (64.7 mmol) of N were added to 10.0 g (64.06 mmol) of uracil-5-carboxylic acid (Aldrich Chemical Company) partially dissolved in 20 mL of DMF under low temperature conditions. N -Diethylaniline, and then the mixture was heated at 90 ° C for 2 hours and 40 minutes. After cooling to room temperature and POCl evaporated after half an excess of 3, the medium was poured into ice and then extracted with ether. The combined ether layers were dried with sodium sulfate, filtered and evaporated. 8.1 g (41.97 mmol) of 2,4-dichloro-5-pyrimidinecarboxylic acid were obtained in 65% yield.

-方法B：- Method B:

向9 g(42.8 mmol)2,4-二氯-5-嘧啶甲酸氯化物(Manchester Organics Limited)於60 mL***中之溶液中添加10 mL水且在35℃下用力攪拌反應混合物1小時。在添加***且藉由沈降分離各相之後，經Na2 SO4 乾燥有機相，過濾且在真空下濃縮。獲得7.7 g無色油狀物，其在空氣中快速凝固且立即按原樣用於下一步中。產率=93%。To a solution of 9 g (42.8 mmol) of 2,4-dichloro-5-pyrimidinecarboxylic acid chloride (Manchester Organics Limited) in 60 mL of diethyl ether was added 10 mL of water and the reaction mixture was vigorously stirred at 35 ° C for 1 hour. After addition of diethyl ether and the phases were separated by settling, dried over Na 2 SO 4 the organic phase was dried, filtered and concentrated in vacuo. 7.7 g of a colorless oil was obtained which quickly solidified in air and was used as it is in the next. Yield = 93%.

2.4：2-氯-4-(乙基胺基)嘧啶甲酸2.4: 2-Chloro-4-(ethylamino)pyrimidinecarboxylic acid

在81.3 mL(0.923 mol)三乙胺存在下將8.1 g(41.97 mmol)2,4-二氯-5-嘧啶甲酸溶解於84 mL THF中。添加3.4 mL 70%乙胺水溶液(41.97 mmol)且在室溫下攪拌混合物1小時45分鐘。在蒸發掉溶劑之後，將殘餘物溶解於水中且緩慢添加1 N HCl水溶液直至pH 2。藉由過濾分離沈澱物，以水且接著以***/戊烷混合物洗滌且在真空下乾燥。獲得7.2 g主要含有2-氯-4-(乙基胺基)嘧啶甲酸之固體且按原樣用於下一步中。8.1 g (41.97 mmol) of 2,4-dichloro-5-pyrimidinecarboxylic acid was dissolved in 84 mL of THF in the presence of 81.3 mL (0.923 mol) of triethylamine. 3.4 mL of a 70% aqueous solution of ethylamine (41.97 mmol) was added and the mixture was stirred at room temperature for 1 hour and 45 minutes. After evaporating the solvent, the residue was dissolved in water and aqueous 1N HCl was slowly added until pH 2. The precipitate was isolated by filtration, washed with water and then with diethyl ether / pentane mixture and dried under vacuum. 7.2 g of a solid mainly containing 2-chloro-4-(ethylamino)pyrimidinecarboxylic acid was obtained and used as it is in the next step.

2.5：2-氯-4-(乙基胺基)嘧啶甲酸氟化物2.5: 2-Chloro-4-(ethylamino)pyrimidinecarboxylic acid fluoride

向含有7.0 g(34.72 mmol)在步驟2.4中製備的酸及5.32 mL(38.19 mmol)三乙胺於98 mL二氯甲烷中之溶液中添加5.89 mL(69.79 mmol)三聚氟化氰。攪拌混合物3小時且以590 mL CH2 Cl2 及190 mL冰冷的NaHCO3 水溶液稀釋溶液。以190 mL冰冷的NaHCO3 水溶液洗滌有機相兩次且經MgSO4 乾燥。隨後在減壓下蒸發掉溶劑。獲得7.0 g呈紅色油狀之預期產物，其緩慢凝固且按原樣用於下一步中。定量產率。To a solution containing 7.0 g (34.72 mmol) of the acid prepared in step 2.4 and 5.32 mL (38.19 mmol) of triethylamine in 98 mL of dichloromethane was added 5.89 mL (69.79 mmol). The mixture was stirred for 3 hours and at 590 mL CH 2 Cl 2 and the solution was diluted with 190 mL of ice-cold aqueous NaHCO 3. The organic phase was washed twice at NaHCO 3 solution and 190 mL of ice-cold dried over MgSO 4. The solvent was then evaporated under reduced pressure. Obtained 7.0 g of the expected product as a red oil which slowly solidified and used in the next step. Quantitative yield.

2.6：7-胺基-2-氯-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺2.6:7-Amino-2-chloro-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide

向已在冰浴上冷卻至2-5℃的6.29 g(74.78 mmol)氰基乙醯胺於140 mL無水DMF中之溶液中逐份添加5.98 g(149.55 mmol)60%氫化鈉。在2-5℃下攪拌混合物15分鐘且接著將此懸浮液快速添加至已在冰浴上預冷卻至2-5℃的14.5 g(71.22 mmol)在步驟2.5中製備的酸氟化物於155 mL無水DMF中之溶液中。在室溫下攪拌混合物隔夜且接著冷卻至2-5℃，且逐份添加2.99 g(74.78 mmol)60%氫化鈉。在室溫下攪拌介質4小時，接著緩慢添加冰以破壞過量氫化物，且將反應介質傾入冰水混合物中。藉由添加0.1 N HCl水溶液酸化所得混合物。藉由過濾分離所形成之沈澱物，以水沖洗且接著在烘箱中乾燥，隨後以戊烷沖洗。最終獲得14.0 g呈淡橙色固體狀之預期產物。產率=73.4%。To a solution of 6.29 g (74.78 mmol) of cyanoacetamide in 140 mL of dry DMF, which had been cooled to 2-5 ° C on an ice-bath, was added portion of 5.78 g (149.55 mmol) of 60% sodium hydride. The mixture was stirred at 2-5 ° C for 15 minutes and then this suspension was quickly added to 14.5 g (71.22 mmol) of the acid fluoride prepared in step 2.5 which had been pre-cooled to 2-5 ° C on an ice bath at 155 mL. In a solution in anhydrous DMF. The mixture was stirred overnight at room temperature and then cooled to 2-5 ° C, and 2.99 g (74.78 mmol) of 60% sodium hydride was added portionwise. The medium was stirred at room temperature for 4 hours, then ice was slowly added to destroy the excess hydride, and the reaction medium was poured into the ice water mixture. The resulting mixture was acidified by the addition of 0.1 N aqueous HCl. The precipitate formed was separated by filtration, rinsed with water and then dried in an oven, followed by rinsing with pentane. Finally, 14.0 g of the expected product was obtained as a pale orange solid. Yield = 73.4%.

2.7：7-胺基-8-乙基-2-[4-(4-甲基哌嗪-1-羰基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺2.7: 7-Amino-8-ethyl-2-[4-(4-methylpiperazine-1-carbonyl)phenylamino]-5-one-5-8-dihydropyrido[2 , 3-d] pyrimidine-6-formamide

將0.3 g(1.12 mmol)在步驟2.6中製備的產物及491 mg(2.24 mmol)在步驟2.2中製備的產物於6 mL NMP中之混合物置於10 mL微波管中。將經密封之管置於微波烘箱(CEM machine，型號Discover)中且在120℃下，在壓力下，在75 W功率下加熱混合物60分鐘，且隨後冷卻至室溫。添加15 mL水且接著添加5 mL NaHCO3 飽和水溶液且藉由抽吸排乾所形成之沈澱物且接著在烘箱中乾燥。藉由矽膠管柱層析，以二氯甲烷/甲醇梯度(100/0至90/10)溶離來純化粗固體。獲得0.055 g呈橙色粉末狀之預期產物。0.3 g (1.12 mmol) of the product prepared in step 2.6 and a mixture of 491 mg (2.24 mmol) of the product obtained in step 2.2 in 6 mL of NMP were placed in a 10 mL microwave tube. The sealed tube was placed in a microwave oven (CEM machine, Model Discover) and the mixture was heated at a power of 75 W for 60 minutes at 120 ° C under pressure and then cooled to room temperature. 15 mL of water was added and then 5 mL of a saturated aqueous solution of NaHCO 3 was added and the formed precipitate was drained by suction and then dried in an oven. The crude solid was purified by hydrazine gel column chromatography eluting with dichloromethane/methanol gradient (100/0 to 90/10). 0.055 g of the expected product was obtained as an orange powder.

m.p.=281℃。M+H+ =451。產率=11%。Mp = 281 °C. M+H + = 451. Yield = 11%.

1 H NMR(DMsO-d6 ,400MHz):δ11.8(寬s,1H);10.3(s,1H);10.2(d,1H);9.0(s,1H);8.0(寬s,1H);7.8(d,2H);7.40(d,2H);7.2(d,1H);4.4(q,2H);3.5(m,4H);3.30(s,3H);2.30(m,4H);1.3(t,3H)。 1 H NMR (DMsO-d 6 , 400MHz): δ11.8 ( broad s, 1H); 10.3 (s , 1H); 10.2 (d, 1H); 9.0 (s, 1H); 8.0 ( broad s, 1H) ; 7.8 (d, 2H); 7.40 (d, 2H); 7.2 (d, 1H); 4.4 (q, 2H); 3.5 (m, 4H); 3.30 (s, 3H); 2.30 (m, 4H); 1.3 (t, 3H).

實例3：7-胺基-8-環戊基-2-(4-嗎啉-4-基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺Example 3: 7-Amino-8-cyclopentyl-2-(4-morpholin-4-ylphenylamino)-5-one-5,8-dihydropyrido[2,3-d Pyrimidine-6-formamide

3.1：2-氯-4-(環戊基胺基)嘧啶甲酸3.1: 2-Chloro-4-(cyclopentylamino)pyrimidinecarboxylic acid

將10 g(51.82 mmol)2,4-二氯-5-嘧啶甲酸於100 mL THF 中之懸浮液於冰浴上冷卻至2-5℃，且逐滴添加5.12 mL(51.82 mmol)環戊胺及21.67 mL(155.45 mmol)三乙胺於40 mL THF中之溶液。在室溫下攪拌混合物2小時。蒸發掉THF且接著以水稀釋殘餘物。以1 N HCl水溶液酸化所得混合物至pH 2且接著以二氯甲烷萃取兩次。合併有機相，經Na2 sO4 乾燥，過濾且在真空下濃縮。以***濕磨所回收之固體，藉由抽吸排乾且在烘箱中乾燥。獲得5.28 g呈米色固體狀之預期產物，其按原樣用於下一步中。產率=42%。A suspension of 10 g (51.82 mmol) of 2,4-dichloro-5-pyrimidinecarboxylic acid in 100 mL of THF was cooled to 2-5 ° C on ice bath and 5.12 mL (51.82 mmol) of cyclopentylamine was added dropwise. And 21.67 mL (155.45 mmol) of triethylamine in 40 mL of THF. The mixture was stirred at room temperature for 2 hours. The THF was evaporated and the residue was diluted with water. The resulting mixture was acidified to pH 2 with 1 N aqueous HCl and then extracted twice with dichloromethane. The combined organic phases were dried over Na 2 sO 4, filtered and concentrated under vacuo. The recovered solid was wet-ground with diethyl ether, drained by suction and dried in an oven. Obtained 5.28 g of the expected product as a beige solid which was used in the next step. Yield = 42%.

3.2：2-氯-4-(環戊基胺基)嘧啶甲酸氟化物3.2: 2-Chloro-4-(cyclopentylamino)pyrimidinecarboxylic acid fluoride

向5.24(21.68 mmol)在步驟3.1中製備的產物於140 mL二氯甲烷中之懸浮液中添加3.02 mL(21.68 mmol)三乙胺且接著添加2.75 mL(35.52 mmol)三聚氟化氰。在室溫下攪拌混合物4小時且以150 mL二氯甲烷稀釋溶液。以200 mL冰冷的NaHCO3 水溶液洗滌有機相三次，經MgSO4 乾燥，過濾且在真空下濃縮。獲得5.2 g呈橙色固體狀之預期產物。產率=98%。To a suspension of 5.24 (21.68 mmol) of the product obtained in step 3.1 in 140 mL of dichloromethane was added 3.02 mL (21.68 mmol) of triethylamine and then 2.75 mL (35.52 mmol) of s. The mixture was stirred at room temperature for 4 hours and the solution was diluted with 150 mL of dichloromethane. In the organic phase three times with 200 mL NaHCO 3 aqueous solution was washed with ice-cooling, dried over MgSO 4, filtered and concentrated under vacuo. Obtained 5.2 g of the expected product as an orange solid. Yield = 98%.

3.3：7-胺基-2-氯-8-環戊基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯3.3:7-Amino-2-chloro-8-cyclopentyl-5-one-5,8-dihydropyrido[2,3-d]pyrimidin-6-formamidine 胺amine

向已於冰浴上冷卻至2-5℃的1.88 g(22.41 mmol)氰基乙醯胺於20 mL無水DMF中之溶液中逐份添加1.8 g(44.82 mmol)60%氫化鈉。在2-5℃下攪拌混合物15分鐘且接著將此懸浮液快速添加至已預冷卻至2-5℃的5.2 g(21.34 mmol)在步驟3.2中製備的酸氟化物於20 mL無水DMF中之溶液中。在室溫下攪拌混合物隔夜且接著於冰浴上冷卻至2-5℃，且逐份添加0.90 g(22.41 mmol)60%氫化鈉。在室溫下攪拌反應混合物3小時且接著傾入冰、100 mL水與150 mL 1 N HCl水溶液之混合物中。藉由過濾分離所形成之黃色沈澱物，以水沖洗且接著在烘箱中乾燥，隨後以戊烷沖洗。最終獲得5.4 g呈橙色粉末狀之含有預期環化產物及非環化產物之混合物。藉由矽膠管柱層析，以二氯甲烷/甲醇梯度(99/1至96/4)溶離來純化混合物。最終獲得0.6 g呈淡黃色固體狀之預期產物。產率=9%。To a solution of 1.88 g (22.41 mmol) of cyanoacetamide in 20 mL of dry DMF, which had been cooled to 2-5 ° C on an ice bath, was added portionwise 1.8 g (44.82 mmol) of 60% sodium hydride. The mixture was stirred at 2-5 °C for 15 minutes and then this suspension was quickly added to 5.2 g (21.34 mmol) of the acid fluoride prepared in step 3.2 pre-cooled to 2-5 ° C in 20 mL anhydrous DMF. In solution. The mixture was stirred at room temperature overnight and then cooled to 2-5 <0>C on an ice bath and 0.90 g (22.41 mmol) of 60% sodium hydride. The reaction mixture was stirred at room temperature for 3 hours and then poured into a mixture of ice, 100 mL water and 150 mL 1 N aqueous HCI. The yellow precipitate formed was separated by filtration, rinsed with water and then dried in an oven, then rinsed with pentane. Finally, 5.4 g of a mixture of the expected cyclized product and the non-cyclized product in the form of an orange powder was obtained. The mixture was purified by ruthenium column chromatography eluting with a dichloromethane/methanol gradient (99/1 to 96/4). Finally, 0.6 g of the expected product was obtained as a pale yellow solid. Yield = 9%.

3.4：7-胺基-8-環戊基-2-(4-嗎啉-4-基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺3.4: 7-Amino-8-cyclopentyl-2-(4-morpholin-4-ylphenylamino)-5-one-5,8-dihydropyrido[2,3-d] Pyrimidine-6-formamide

將184 mg(0.60 mmol)在步驟3.3中製備的產物與0.266 g(1.49 mmol)N -(4-胺基苯基)嗎啉(Lancaster)於6 mL NMP中之混合物置於10 mL微波管中。將經密封之管置於微波烘箱(CEM machine，型號Discover)中且在90℃下，在壓力下，在100 W之功率下加熱混合物1小時且接著冷卻至室溫。添加20 mL水且接著添加5 mL NaHCO3 飽和水溶液，且藉由抽吸排乾所形成之沈澱物並在烘箱中乾燥。藉由矽膠管柱層析，以二氯甲烷/甲醇梯度(98/2至95/5)溶離來純化粗固體。獲得0.065 g呈米色粉末狀之預期產物。產率=24%。m.p.=265℃。M+H+ =450。A mixture of 184 mg (0.60 mmol) of the product prepared in step 3.3 and 0.266 g (1.49 mmol) of N- (4-aminophenyl)morpholine (Lancaster) in 6 mL of NMP was placed in a 10 mL microwave tube. . The sealed tube was placed in a microwave oven (CEM machine, Model Discover) and the mixture was heated at 90 ° C under pressure at a power of 100 W for 1 hour and then cooled to room temperature. 20 mL of water was added and then 5 mL of a saturated aqueous solution of NaHCO 3 was added, and the formed precipitate was drained by suction and dried in an oven. The crude solid was purified by hydrazine gel column chromatography eluting with dichloromethane/methanol gradient (98/2 to 95/5). 0.065 g of the expected product was obtained as a beige powder. Yield = 24%. Mp = 265 ° C. M+H + = 450.

1 H NMR(DMSO-d6 ,400 MHz):δ11.5-12.5(極寬s,1H);10.4(d,1H);9.6(s,1H);8.9(s,1H);7.4(d,2H);7.1(d,1H);6.9(d,2H),5.0(m,1H);3.7(m,4H);3.0(m,4H);2.2-2.5(m,2H);1.3-1.9(m,6H)。 1 H NMR (DMSO-d 6 , 400 MHz): δ 11.5-12.5 (ext. s, 1H); 10.4 (d, 1H); 9.6 (s, 1H); 8.9 (s, 1H); , 2H); 7.1 (d, 1H); 6.9 (d, 2H), 5.0 (m, 1H); 3.7 (m, 4H); 3.0 (m, 4H); 2.2-2.5 (m, 2H); 1.9 (m, 6H).

實例4：7-胺基-8-乙基-2-(2-甲氧基-4-哌啶-4-基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽Example 4: 7-Amino-8-ethyl-2-(2-methoxy-4-piperidin-4-ylphenylamino)-5-one-5-8-dihydropyridinium [ 2,3-d]pyrimidine-6-methanamine hydrochloride

4.1：4-溴-2-甲氧基-1-硝基苯4.1: 4-bromo-2-methoxy-1-nitrobenzene

將18.4 g(83.64 mmol)2-氟-4-溴硝基苯(Aldrich)幾乎完全溶解於300 mL無水甲醇中。逐滴添加19.9 mL(106.22 mmol)30%甲醇鈉之甲醇溶液且在室溫下攪拌混合物隔夜。在減壓下蒸發掉甲醇，將介質溶解於乙酸乙酯及水中，且隨後藉由添加1 N HCl水溶液酸化水相。在藉由沈降分離各相之後，以NaCl飽和水溶液洗滌有機相，經Na2 SO4 乾燥，過濾且在真空下濃縮。獲得17.4 g呈黃色固體狀之預期產物。產率=89.7%。18.4 g (83.64 mmol) of 2-fluoro-4-bromonitrobenzene (Aldrich) was almost completely dissolved in 300 mL of anhydrous methanol. 19.9 mL (106.22 mmol) of 30% sodium methoxide in methanol was added dropwise and the mixture was stirred at room temperature overnight. The methanol was evaporated under reduced pressure, the medium was dissolved in ethyl acetate and water, and then the aqueous phase was acidified by adding 1 N aqueous HCl. After the phases were separated by settling, the organic phase was washed in a saturated aqueous NaCl, dried over Na 2 SO 4, filtered and concentrated in vacuo. 17.4 g of the expected product are obtained as a yellow solid. Yield = 89.7%.

4.2：4-(3-甲氧基-4-硝基苯基)-3,6-二氫-2H-吡啶-1-甲酸第三丁酯4.2: 4-(3-methoxy-4-nitrophenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

向4.64 g(20.0 mmol)在步驟4.1中製備的產物、6.25 g(20.2 mmol)3,6-二氫-2H -吡啶-1-N-Boc-4-酸四甲基乙二醇酯(Frontier Scientific)及8.29 g(60.0 mmol)碳酸鉀於125 mL無水DMF中之混合物中鼓入氬氣持續10分鐘。添加0.98 g(1.2 mmol)PdCl2 dppf‧CH2 Cl2 且在90℃下，在氬氣下加熱混合物3小時。以乙酸乙酯稀釋所得混合物且以水洗滌兩次且以NaCl飽和水溶液洗滌一次。經Na2 SO4 乾燥有機相，過濾且在真空下濃縮。藉由矽膠管柱層析，以環己烷/乙酸乙酯梯度(75/25至70/30)溶離來純化所獲粗固體。獲得6.02 g淡黃色固體，且在環己烷中濕磨且接著藉由抽吸排乾並在烘箱中乾燥。最終回收5.89 g呈白色固體狀之預期產物。產率=88%。4.64 g (20.0 mmol) of the product prepared in step 4.1, 6.25 g (20.2 mmol) of 3,6-dihydro- 2H -pyridin-1-N-Boc-4- Argon was bubbled through a mixture of acid tetramethyl glycol ester (Frontier Scientific) and 8.29 g (60.0 mmol) potassium carbonate in 125 mL of anhydrous DMF for 10 minutes. 0.98 g (1.2 mmol) of PdCl 2 dppf ‧ CH 2 Cl 2 was added and the mixture was heated under argon at 90 ° C for 3 hours. The resulting mixture was diluted with ethyl acetate and washed twice with water and once with saturated aqueous NaCI. Dried over Na 2 SO 4 organic phase was filtered and concentrated in vacuo. The crude solid obtained was purified by column chromatography on silica gel eluting with hexane/ethyl acetate gradient (75/25 to 70/30). 6.02 g of a pale yellow solid were obtained, wet-milled in cyclohexane and then drained by suction and dried in oven. Finally, 5.89 g of the expected product was obtained as a white solid. Yield = 88%.

4.3：4-(4-胺基-3-甲氧基苯基)哌啶-1-甲酸第三丁酯4.3: 4-butyl 4-(4-amino-3-methoxyphenyl)piperidine-1-carboxylate

將於130 mL乙酸乙酯/乙醇混合物(v/v=1/1)中的4.27 g(12.77 mmol)在步驟4.2中製備的產物置於氫化高壓釜中，且在惰性氛圍下添加0.54 g 10%鈀/木炭。在室溫下，在3巴之氫氣壓力下攪拌混合物。在經由薄玻璃纖維紙過濾且在減壓下蒸發之後，獲得3.87 g呈粉色固體狀之預期產物，其按原樣用於下一步中。產率=99%。4.27 g (12.77 mmol) of the product prepared in step 4.2 in 130 mL of ethyl acetate/ethanol mixture (v/v = 1/1) was placed in a hydrogenation autoclave and 0.54 g of 10 was added under an inert atmosphere. % palladium / charcoal. The mixture was stirred at room temperature under a hydrogen pressure of 3 bar. After filtration through a thin glass fiber paper and evaporation under reduced pressure, 3.87 g of the desired product as a white solid was obtained, which was used in the next. Yield = 99%.

4.4：4-[4-(7-胺基-6-胺甲醯基-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-2-基胺基)-3-甲氧基苯基]哌啶-1-甲酸第三丁酯4.4: 4-[4-(7-Amino-6-aminocarbamido-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-2-yl Amino)-3-methoxyphenyl]piperidine-1-carboxylic acid tert-butyl ester

將0.45 g(1.63 mmol)在步驟2.6中製備的產物與1.00 g(3.25 mmol)在步驟4.3中製備的產物於3 mL NMP中之混合物置於圓底燒瓶中。在110℃下加熱懸浮液3小時。添加30 mL水且接著添加5 mL NaHCO3 飽和水溶液並藉由抽吸排乾所形成之沈澱物且接著在烘箱中乾燥。藉由矽膠管柱層析，以二氯甲烷/甲醇梯度(100/0至93/7)溶離來純化粗固體。獲得0.52 g呈米色粉末狀之預期產物。產率=59.5%。A mixture of 0.45 g (1.63 mmol) of the product prepared in step 2.6 and 1.00 g (3.25 mmol) of the product obtained in step 4.3 in 3 mL of NMP was placed in a round bottom flask. The suspension was heated at 110 ° C for 3 hours. 30 mL of water was added and then 5 mL of a saturated aqueous solution of NaHCO 3 was added and the formed precipitate was drained by suction and then dried in an oven. The crude solid was purified by hydrazine gel column chromatography eluting with dichloromethane/methanol gradient (100/0 to 93/7). 0.52 g of the expected product was obtained as a beige powder. Yield = 59.5%.

4.54.5 ：7-胺基-8-乙基-2-(2-甲氧基-4-哌啶-4-基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽:7-Amino-8-ethyl-2-(2-methoxy-4-piperidin-4-ylphenylamino)-5-keto-5,8-dihydropyrido[2, 3-d]pyrimidine-6-methanamine hydrochloride

將0.51 g(0.95 mmol)在步驟4.4中製備的產物懸浮於10 mL二氯甲烷/甲醇混合物(v/v=8/2)中，且添加3.55 mL(14.20 mmol)4N氯化氫之二噁烷溶液。在室溫下攪拌混合物隔夜，且添加***。藉由抽吸排乾固體，以戊烷沖洗且在烘箱中乾燥。獲得0.48 g呈米色固體狀之預期產物，其按原樣用於下一步中。產率(二鹽酸鹽)=99.1%。m.p.=117℃。M+H+ =408。0.51 g (0.95 mmol) of the product prepared in step 4.4 was suspended in 10 mL of dichloromethane/methanol mixture (v/v = 8/2), and 3.55 mL (14.20 mmol) of 4N hydrogen chloride in dioxane was added. . The mixture was stirred at room temperature overnight and diethyl ether was added. The solid was drained by suction, rinsed with pentane and dried in an oven. 0.48 g of the expected product was obtained as a beige solid which was used in the next step. Yield (dihydrochloride) = 99.1%. Mp = 117 ° C. M+H + = 408.

1 H NMR(DMSO-d6;400 MHz):δ11.8(寬s,1H);10.4(極寬s,<1H);10.2(s,1H);9.0(s,1H);8.9(寬s,1H);8.1(寬s,1H);7.8(d,1H)57.2(d,1H);4.3(q,2H);3.4(m,2H),3.0(m,2H);2.8(m,1H);1.9(m,4H);1.3(t,3H)。 1 H NMR (DMSO-d6; 400 MHz): δ 11.8 (width s, 1H); 10.4 (ext. s, <1H); 10.2 (s, 1H); 9.0 (s, 1H); , 1H); 8.1 (width s, 1H); 7.8 (d, 1H) 57.2 (d, 1H); 4.3 (q, 2H); 3.4 (m, 2H), 3.0 (m, 2H); 2.8 (m, 1H); 1.9 (m, 4H); 1.3 (t, 3H).

實例5：7-胺基-8-乙基-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-N-甲基-甲醯胺鹽酸鹽Example 5: 7-Amino-8-ethyl-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]phenylamino }-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-N-methyl-methanoamine hydrochloride

5.1：7-胺基-8-乙基-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-N- 甲基甲醯胺 5.1: 7-Amino-8-ethyl-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]phenylamino} -5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-N -methylformamide

將0.47 g(0.92 mmol)在步驟4.5中製備的鹽酸鹽懸浮於7.8 mL二氯甲烷/冰醋酸混合物(v/v=5/1)中且逐份添加3,3,3-三氟丙醛鈉(Alfa Aesar)及接著添加三乙醯氧基硼氫化鈉。攪拌反應混合物2.5小時且接著傾入50 mL NaHCO3 水溶液中。藉由過濾分離固體，且藉由矽膠管柱層析，以二氯甲烷/甲醇梯度(100/0至90/10)溶離來純化其。在***中濕磨之後，最終獲得0.25 g呈米色固體狀之預期產物。產率=50.9%。0.47 g (0.92 mmol) of the hydrochloride salt prepared in step 4.5 was suspended in 7.8 mL of dichloromethane/glacial acetic acid mixture (v/v = 5/1) and 3,3,3-trifluoropropane was added portionwise. Sodium aldehyde (Alfa Aesar) followed by sodium triethoxy borohydride. The reaction mixture was stirred for 2.5 hours and then poured into 50 mL NaHCO 3 solution. The solid was isolated by filtration and purified by silica gel column chromatography eluting with dichloromethane/methanol gradient (100/0 to 90/10). After wet milling in diethyl ether, 0.25 g of the desired product was obtained as a beige solid. Yield = 50.9%.

5.2：7-胺基-8-乙基-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-N-甲基甲醯胺鹽酸鹽5.2: 7-Amino-8-ethyl-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]phenylamino} -5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-N-methylformamide hydrochloride

將0.19 g(0.36 mmol)在步驟4.6中製備的產物溶解於4 mL二氯甲烷/甲醇混合物(v/v=4/1)中，且添加1.09 mL(1.09 mmol)1.0 M於***中之氯化氫。攪拌懸浮液5分鐘且接著以***稀釋，且藉由抽吸排乾沈澱物，以***及戊烷沖洗並在真空下乾燥。獲得0.22 g呈黃褐色粉末狀之預期產物。產率(二鹽酸鹽)=96.5%。m.p.=199℃。M+H+ =534。0.19 g (0.36 mmol) of the product prepared in step 4.6 was dissolved in 4 mL dichloromethane / methanol mixture (v / v = 4 / 1), and 1.09 mL (1.09 mmol) of 1.0 M hydrogen chloride in diethyl ether was added. . The suspension was stirred for 5 minutes and then diluted with diethyl ether and the precipitate was dried with suction, washed with diethyl ether and pentane and dried under vacuum. Obtained 0.22 g of the expected product as a tan powder. Yield (dihydrochloride) = 96.5%. Mp = 199 ° C. M+H + =534.

1 H NMR(DMSO-d6;400 MHz):δ11.8(寬s,1H);11.2(極寬s,<1H);10.3(寬s,1H);9.0(s,1H);8.8(s,1H);8.1(寬s,1H);7.9(d,1H);7.2(極寬s,<1H);7.0(s,1H);6.9(d,1H);4.3(q,2H);3.9(s,3H);3.6(m,2H),3.4(m,2H);3.0-3.2(m,2H);2.9(m,1H);2.0(m,4H);1.3(t,3H)。 1 H NMR (DMSO-d6; 400 MHz): δ 11.8 (width s, 1H); 11.2 (ext. s, <1H); 10.3 (width s, 1H); 9.0 (s, 1H); , 1H); 8.1 (width s, 1H); 7.9 (d, 1H); 7.2 (extremely wide s, <1H); 7.0 (s, 1H); 6.9 (d, 1H); 4.3 (q, 2H); 3.9 (s, 3H); 3.6 (m, 2H), 3.4 (m, 2H); 3.0-3.2 (m, 2H); 2.9 (m, 1H); 2.0 (m, 4H); 1.3 (t, 3H) .

實例6：7-胺基-2-[4-(1-環丙基哌啶-4-基)-2-甲氧基苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽Example 6: 7-Amino-2-[4-(1-cyclopropylpiperidin-4-yl)-2-methoxyphenylamino]-8-ethyl-5-one-5, 8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide hydrochloride

6.1：7-胺基-2-[4-(1-環丙基哌啶-4-基)-2-甲氧基苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺6.1: 7-Amino-2-[4-(1-cyclopropylpiperidin-4-yl)-2-methoxyphenylamino]-8-ethyl-5-one-5-8 -dihydropyrido[2,3-d]pyrimidine-6-carboxamide

將在步驟4.5中製備的鹽酸鹽藉由以1 N NaOH水溶液處理，接著過濾且在烘箱中乾燥而轉化為鹼形式。將0.44 g(1.0 mmol)此產物懸浮於10 mL無水甲醇中。添加0.57 mL(10.0 mmol)冰醋酸、3已在真空下預乾燥之分子篩、0.9 mL(4.5 mmol)(1-乙氧基環丙氧基)三甲基矽烷及0.188 g(3.0 mmol)氰基硼氫化鈉。在80℃下加熱混合物1小時，且添加2 mL四氫呋喃及再添加0.45 mL(2.25 mmol)(1-乙氧基環丙氧基)三甲基矽烷。在80℃下加熱反應混合物20小時且接著使其冷卻至室溫並蒸發至乾燥。藉由矽膠管柱層析，以二氯甲烷/甲醇梯度(96/4至90/10)溶離來純化所獲殘餘物。在***/異丙醇混合物(v/v=3/1)中濕磨且接著在乙酸乙酯/異丙醇中濕磨之後，最終獲得0.126 g呈白色固體狀之預期產物。產率=26%。The hydrochloride salt prepared in step 4.5 was converted to the base form by treatment with 1 N aqueous NaOH solution, followed by filtration and drying in an oven. 0.44 g (1.0 mmol) of this product was suspended in 10 mL of anhydrous methanol. Add 0.57 mL (10.0 mmol) glacial acetic acid, 3 Molecular sieves which had been pre-dried under vacuum, 0.9 mL (4.5 mmol) of (1-ethoxycyclopropoxy)trimethylnonane and 0.188 g (3.0 mmol) of sodium cyanoborohydride. The mixture was heated at 80 ° C for 1 hour, and 2 mL of tetrahydrofuran was added followed by 0.45 mL (2.25 mmol) of (1-ethoxycyclopropoxy)trimethylnonane. The reaction mixture was heated at 80 ° C for 20 hours and then allowed to cool to room temperature and evaporated to dryness. The residue obtained was purified by hydrazine gel column chromatography eluting with dichloromethane/methanol gradient (96/4 to 90/10). After wet milling in an ether/isopropanol mixture (v/v = 3/1) followed by wet-milling in ethyl acetate/isopropanol, 0.126 g of the desired product was obtained as a white solid. Yield = 26%.

6.2：7-胺基-2-[4-(1-環丙基哌啶-4-基)-2-甲氧基苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽6.2: 7-Amino-2-[4-(1-cyclopropylpiperidin-4-yl)-2-methoxyphenylamino]-8-ethyl-5-one-5,8 -dihydropyrido[2,3-d]pyrimidin-6-carboxamide hydrochloride

向0.126 g(0.26 mmol)在步驟7.1中製備的產物於2.6 mL甲醇中之懸浮液中添加0.79 mL(0.79 mmol)1.0 M氫氯醚。在室溫下攪拌混合物5分鐘且接著以***稀釋。藉由抽吸排乾沈澱物，以***及戊烷沖洗且在真空下乾燥。獲得0.133 g呈米色固體狀之預期產物。產率(二鹽酸鹽)=92%。m.p.=226-228℃。M+H+ =478。To a suspension of 0.126 g (0.26 mmol) of the product obtained in step 7.1 in 2.6 mL of methanol was added 0.79 mL (0.79 mmol) of 1.0 M hydrochloroether. The mixture was stirred at room temperature for 5 minutes and then diluted with diethyl ether. The precipitate was drained by suction, rinsed with diethyl ether and pentane and dried under vacuum. 0.133 g of the expected product was obtained as a beige solid. Yield (dihydrochloride) = 92%. Mp = 226-228 °C. M+H + = 478.

1 H NMR(DMSO-d6 ,400 MHz):δ11.8(寬s,1H);10.6(寬s,~0.5H);10.4(寬s,~1.5H);9.0(s,1H);8.8(s,1H);8.1(寬s,1H);7.9(d,1H);7.2(極寬s,<1H);7.0(s,1H);6.9(d,1H);4.3(q,2H);3.9(s,3H);3.6(m,2H);2.8-3.4(m,4H);2.0-2.2(m,4H);1.30(t,3H);1.20(m,2H);0.80(m;2H)。 1 H NMR (DMSO-d 6 , 400 MHz): δ 11.8 (width s, 1H); 10.6 (width s, ~0.5H); 10.4 (width s, ~1.5H); 9.0 (s, 1H); 8.8 (s, 1H); 8.1 (width s, 1H); 7.9 (d, 1H); 7.2 (extremely wide s, <1H); 7.0 (s, 1H); 6.9 (d, 1H); 4.3 (q, 2H); 3.9 (s, 3H); 3.6 (m, 2H); 2.8-3.4 (m, 4H); 2.0-2.2 (m, 4H); 1.30 (t, 3H); 1.20 (m, 2H); (m; 2H).

實例7:7-胺基-8-乙基-2-(3-嗎啉-4-基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺Example 7: 7-Amino-8-ethyl-2-(3-morpholin-4-ylphenylamino)-5-one-5,8-dihydropyrido[2,3-d] Pyrimidine-6-formamide

將0.25 g(0.93 mmol)在步驟2.6中製備的產物與0.33 g(1.87 mmol)3-嗎啉-4-基苯胺於4 mL NMP中之混合物置於10 mL微波管中。將經密封之管置於微波烘箱(CEM machine，型號Discover)中且將混合物在100 W之功率下，在壓力下在90℃下加熱30分鐘，在120℃下加熱1小時，且接著冷卻至室溫。添加20 mL水及接著添加5 mL NaHCO3 飽和水溶液且藉由抽吸排乾所形成之沈澱物且接著在烘箱中乾燥。在甲醇中濕磨粗固體，藉由抽吸排乾，以***及戊烷沖洗並在真空下乾燥。最終獲得0.16 g呈米色粉末狀之預期產物。產率=41.8%。m.p.=195℃。M+H+ =410。A mixture of 0.25 g (0.93 mmol) of the product prepared in step 2.6 and 0.33 g (1.87 mmol) of 3-morpholin-4-ylaniline in 4 mL of NMP was placed in a 10 mL microwave tube. The sealed tube was placed in a microwave oven (CEM machine, Model Discover) and the mixture was heated at 90 W for 30 minutes at 90 ° C under pressure, heated at 120 ° C for 1 hour, and then cooled to Room temperature. 20 mL of water was added followed by 5 mL of a saturated aqueous solution of NaHCO 3 and the resulting precipitate was drained by suction and then dried in an oven. The crude solid was wet-milled in methanol, drained by suction, washed with diethyl ether and pentane and dried under vacuum. Finally, 0.16 g of the expected product was obtained as a beige powder. Yield = 41.8%. Mp = 195 ° C. M+H + =410.

1 H NMR(DMSO-d6 ,400 MHz):δ11.8(寬s,1H);10.3(d,1H);10.0(寬s,1H);8.9(s,1H);8.0(極寬s,<1H);7.3(m,2H);7.1-7.3(m,3H);6.6(d,1H),4.4(q,2H);3.7(m,4H);3.1(m,4H);1.2(t,3H) 1 H NMR (DMSO-d 6 , 400 MHz): δ 11.8 (width s, 1H); 10.3 (d, 1H); 10.0 (width s, 1H); 8.9 (s, 1H); 8.0 (ext. , <1H); 7.3 (m, 2H); 7.1-7.3 (m, 3H); 6.6 (d, 1H), 4.4 (q, 2H); 3.7 (m, 4H); 3.1 (m, 4H); (t, 3H)

實例8：2-[4-(4-乙醯基哌嗪-1-基)苯基胺基]-7-胺基-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺Example 8: 2-[4-(4-Ethylpiperazin-1-yl)phenylamino]-7-amino-8-ethyl-5-one-5,8-dihydropyridine [2,3-d]pyrimidine-6-carboxamide

8.1：1-[4-(4-硝基苯基)哌嗪-1-基]乙酮8.1:1-[4-(4-Nitrophenyl)piperazin-1-yl]ethanone

將5.0 g(35.44 mmol)1-氟-4-硝基苯及4.99 g(38.98 mmol)N-乙醯基哌嗪於50 mL乙腈中之溶液在60℃下加熱15小時。以水及乙酸乙酯稀釋所得混合物。在藉由沈降分離各相且以乙酸乙酯萃取水相之後，合併有機相，經Na2 SO4 乾燥，過濾且在真空下濃縮。獲得7.7 g呈黃色固體狀之預期產物，其按原樣用於下一步中。產率=88.8%。A solution of 5.0 g (35.44 mmol) of 1-fluoro-4-nitrobenzene and 4.99 g (38.98 mmol) of N-ethinylpiperazine in 50 mL of acetonitrile was heated at 60 ° C for 15 hours. The resulting mixture was diluted with water and ethyl acetate. After the phases were separated by settling and the aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over Na 2 SO 4, filtered and concentrated in vacuo. Obtained 7.7 g of the expected product as a yellow solid which was used in the next step. Yield = 88.8%.

8.2：1-[4-(4-胺基苯基)哌嗪-1-基]乙酮8.2: 1-[4-(4-Aminophenyl)piperazin-1-yl]ethanone

將於40 mL乙酸乙酯中之3.0 g(12.04 mmol)在步驟8.1中製備的產物置於氫化高壓釜中，且在惰性氛圍下添加0.15 g 10%鈀/木炭。在室溫下，在5巴氫氣壓力下攪拌混合物。在經由矽藻土過濾且在減壓下蒸發之後，獲得1.6 g呈米色固體狀之預期產物，其按原樣用於下一步中。產率=61%。3.0 g (12.04 mmol) of the product prepared in step 8.1 in 40 mL of ethyl acetate was placed in a hydrogenation autoclave, and 0.15 g of 10% palladium/charcoal was added under an inert atmosphere. The mixture was stirred at 5 bar of hydrogen pressure at room temperature. After filtration through celite and evaporation under reduced pressure, 1.6 g of the desired product as a beige solid was obtained, which was used in the next step. Yield = 61%.

88 .3：2-[4-(4-乙醯基哌嗪-1-基)苯基胺基]-7-胺基-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺.3: 2-[4-(4-Ethylpiperazin-1-yl)phenylamino]-7-amino-8-ethyl-5-one-5,8-dihydropyridine [2,3-d]pyrimidine-6-carboxamide

將0.30 g(1.12 mmol)在步驟2.6中製備的產物與0.49 g(2.24 mmol)在步驟8.2中製備的產物於5 mL NMP中之混合物置於10 mL微波管中。將經密封之管置於微波烘箱(CEM machine，型號Discover)中且將混合物在100 W之功率下，在90℃下在壓力下加熱30分鐘，且接著冷卻至室溫。添加20 mL水及接著添加5 mL NaHCO3 飽和水溶液，且藉由抽吸排乾所形成之沈澱物並在烘箱中乾燥。於甲醇中濕磨粗固體，藉由抽吸排乾，以***及戊烷沖洗並在真空下乾燥。最終獲得0.30 g呈米色粉末狀之預期產物。產率=60%。m.p.=179℃。M+H+ =548。0.30 g (1.12 mmol) of the product prepared in step 2.6 was placed in a 10 mL microwave tube with a mixture of 0.49 g (2.24 mmol) of the product obtained in step 8.2 in 5 mL of NMP. The sealed tube was placed in a microwave oven (CEM machine, Model Discover) and the mixture was heated under pressure at 100 W for 30 minutes at 90 ° C and then cooled to room temperature. 20 mL of water was added followed by 5 mL of a saturated aqueous solution of NaHCO 3 , and the formed precipitate was drained by suction and dried in an oven. The crude solid was wet-milled in methanol, drained by suction, washed with diethyl ether and pentane and dried under vacuum. Finally, 0.30 g of the expected product was obtained as a beige powder. Yield = 60%. Mp = 179 °C. M+H + = 548.

1 H NMR(DMSO-d6 ,400 MHz):δ11.7(極寬s,<1H);10.4(d,1H),9.9(s,1H);8.9(s,1H);8.0(極寬s,<1H);7.6(d,2H);7.1(d,1H);6.9(d,2H);4.4(q,2H);3.6(m,4H);3.1(m,4H);2.0(s,3H);1.3(t,3H) 1 H NMR (DMSO-d 6 , 400 MHz): δ 11.7 (ext. s, <1H); 10.4 (d, 1H), 9.9 (s, 1H); 8.9 (s, 1H); s, <1H); 7.6 (d, 2H); 7.1 (d, 1H); 6.9 (d, 2H); 4.4 (q, 2H); 3.6 (m, 4H); 3.1 (m, 4H); s,3H);1.3(t,3H)

實例9：7-胺基-2-[4-(環丙烷羰基甲基胺基)苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺Example 9: 7-Amino-2-[4-(cyclopropanecarbonylmethylamino)phenylamino]-8-ethyl-5-one-5,8-dihydropyrido[2,3 -d]pyrimidine-6-formamide

9.1：甲基-(4-硝基苯基)環丙烷甲醯胺9.1: Methyl-(4-nitrophenyl)cyclopropanecarbamide

向2.0 g(13.14 mmol)N -甲基-4-硝基苯胺(Aldrich)及1.59 mL(19.72 mmol)吡啶於15 mL四氫呋喃中之溶液中緩慢添加1.43 mL(15.77 mmol)環丙醯氯。將混合物回流2小時且蒸發至乾燥。將殘餘物溶解於乙酸乙酯/水混合物中且隨後經Na2 SO4 乾燥有機相，過濾且在真空下濃縮。獲得呈黃色油狀之預期產物，其按原樣用於下一步中。To a solution of 2.0 g (13.14 mmol) of N -methyl-4-nitroaniline (Aldrich) and 1.59 mL (19.72 mmol) of pyridine in 15 mL of tetrahydrofuran was slowly added 1.43 mL (15.77 mmol). The mixture was refluxed for 2 hours and evaporated to dryness. The residue was dissolved in ethyl acetate / water mixture and then dried over Na 2 SO 4 organic phase was filtered and concentrated in vacuo. The expected product was obtained as a yellow oil which was used in the next step.

9.2：甲基-(4-胺基苯基)環丙烷甲醯胺9.2: Methyl-(4-aminophenyl)cyclopropanecarbamide

向3.56 g(54.49 mmol)鋅粉末於15 mL 33%濃NH4 OH水溶液中之懸浮液中添加溶解於15 mL四氫呋喃中的1.2 g(5.45 mmol)在步驟9.1中製備的產物。在室溫下攪拌混合物1小時，隨後藉由過濾分離出鋅且以***萃取混合物。合併有機相，經Na2 SO4 乾燥，過濾且在真空下濃縮。藉由矽膠管柱層析，以環己烷/乙酸乙酯梯度(70/30至60/40)溶離來純化油狀殘餘物。獲得3 g呈黃色油狀之預期產物。定量產率。(54.49 mmol) 3.56 g of zinc powder is added to the aqueous solution in 15 mL of 33% conc. NH 4 OH was dissolved in the suspension of the product prepared in step 9.1 in 15 mL of tetrahydrofuran 1.2 g (5.45 mmol). The mixture was stirred at room temperature for 1 hour, then zinc was separated by filtration and the mixture was extracted with diethyl ether. The combined organic phases were dried over Na 2 SO 4, filtered and concentrated in vacuo. The oily residue was purified by column chromatography eluting with hexane/ethyl acetate gradient (70/30 to 60/40). 3 g of the expected product are obtained as a yellow oil. Quantitative yield.

9.3：7-胺基-2-[4-(環丙烷羰基甲基胺基)苯基胺基]-8-乙9.3: 7-Amino-2-[4-(cyclopropanecarbonylmethylamino)phenylamino]-8-B 基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide

將0.30 g(1.12 mmol)在步驟2.6中製備的產物與0.43 g(2.24 mmol)在步驟9.2中製備的產物於4.5 mL NMP中之混合物在90℃下加熱3小時。在添加水之後，不形成沈澱物。使混合物在室溫下靜置48小時，且藉由抽吸排乾所形成之沈澱物。在二氯甲烷中濕磨之後，獲得0.17 g呈固體狀之預期產物。m.p.=248℃。M+H+ =422。產率=36%。0.30 g (1.12 mmol) of the product prepared in step 2.6 and 0.43 g (2.24 mmol) of the product obtained in step 9.2 in 4.5 mL of NMP were heated at 90 ° C for 3 hours. No precipitate formed after the addition of water. The mixture was allowed to stand at room temperature for 48 hours, and the precipitate formed was drained by suction. After wet milling in dichloromethane, 0.17 g of the desired product was obtained as a solid. Mp = 248 °C. M+H + =422. Yield = 36%.

1 H NMR(DMSO-d6 ,400 MHz):δ11.8(極寬s,<1H);10.2-10.4(m,2H),9.0(s,1H);8.0(極寬s,<1H);7.8(d,2H);7.4(d,1H);7.2(d,1H);4.3(q,2H);3.1(s,3H);1.4(m,1H);1.2(t,3H);0.8(m,2H);0.6(m,2H) 1 H NMR (DMSO-d 6 , 400 MHz): δ 11.8 (extreme width s, <1H); 10.2-10.4 (m, 2H), 9.0 (s, 1H); 8.0 (ext. s, <1H) ; 7.8 (d, 2H); 7.4 (d, 1H); 7.2 (d, 1H); 4.3 (q, 2H); 3.1 (s, 3H); 1.4 (m, 1H); 1.2 (t, 3H); 0.8 (m, 2H); 0.6 (m, 2H)

實例10：7-胺基-8-乙基-2-[4-(4-乙基哌嗪-1-基)-2-氟-6-甲氧基苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽Example 10: 7-Amino-8-ethyl-2-[4-(4-ethylpiperazin-1-yl)-2-fluoro-6-methoxyphenylamino]-5-one -5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide hydrochloride

10.1：1.5-二氟-3-甲氧基-2-硝基苯10.1: 1.5-Difluoro-3-methoxy-2-nitrobenzene

向2.45 g(14.0 mmol)1,3,5-三氟-2-硝基苯於丙酮中之溶液中連續添加2.9 g(21.0 mmol)K2 CO3 粉末及3.5 mL(56.0 mmol)碘甲烷。在50℃下加熱反應混合物2小時且接著過濾並蒸發至乾燥。將殘餘物溶解於乙酸乙酯中且以水及NaCl飽和水溶液洗滌。經Na2 SO4 乾燥有機相，過濾且在真空下濃縮。回收2.52 g呈黃色固體狀之預期產物，其按原樣用於下一步中。產率=95%。To a solution of 2.45 g (14.0 mmol) of 1,3,5-trifluoro-2-nitrobenzene in acetone was continuously added 2.9 g (21.0 mmol) of K 2 CO 3 powder and 3.5 mL (56.0 mmol) of iodomethane. The reaction mixture was heated at 50 °C for 2 hours and then filtered and evaporated to dryness. The residue was dissolved in ethyl acetate and washed with water and saturated aqueous NaCI. Dried over Na 2 SO 4 organic phase was filtered and concentrated in vacuo. 2.52 g of the expected product was obtained as a yellow solid which was used in the next step. Yield = 95%.

10.2：4-(3-氟-5-甲氧基-4-硝基苯基)哌嗪-1-甲酸第三丁酯10.2: 4-(3-Fluoro-5-methoxy-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester

向2.48 g(13.1 mmol)在步驟10.1中製備的產物於26 mL乙腈中之溶液中添加2.43 g(13.1 mmol)哌嗪甲酸第三丁酯及3.36 mL(19.65 mmol)二異丙基乙胺。在90℃下加熱反應混合物20小時。將其以乙酸乙酯稀釋且以水及接著NaCl飽和水溶液洗滌。藉由矽膠管柱層析，以環己烷/乙酸乙酯梯度(85/15至50/50)溶離來純化粗固體。分離3.25 g主要含有區位異構物4-(5-氟-3-甲氧基-2-硝基苯基)哌嗪-1-甲酸第三丁酯之溶離份。在矽膠管柱上以二氯甲烷/乙酸乙酯梯度(96/4至94/6)溶離，再次純化不純的第二溶離份。最終獲得0.985 g呈黃色固體狀之預期產物。產率=21%。2.48 g (13.1 mmol) of piperazinecarboxylic acid tert-butyl ester and 3.36 mL (19.65 mmol) of diisopropylethylamine were added to a solution of 2.48 g (13.1 mmol) of the product obtained in step 10.1 in 26 mL of acetonitrile. The reaction mixture was heated at 90 ° C for 20 hours. It was diluted with ethyl acetate and washed with water and then a saturated aqueous solution of NaCl. The crude solid was purified by hydrazine gel column chromatography eluting with cyclohexane / ethyl acetate gradient (85 / 15 to 50 / 50). 3.25 g of the isolated fraction containing the positional isomer 4-(5-fluoro-3-methoxy-2-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester was isolated. The impure second fraction was again purified by dissolving on a silica gel column with a gradient of dichloromethane/ethyl acetate (96/4 to 94/6). Finally, 0.985 g of the expected product was obtained as a yellow solid. Yield = 21%.

10.3：4-(4-胺基-3-氟-5-甲氧基苯基)哌嗪-1-甲酸第三丁酯10.3: 4-(4-Amino-3-fluoro-5-methoxyphenyl)piperazine-1-carboxylic acid tert-butyl ester

將於55 mL乙酸乙酯/乙醇混合物(v/v=1/1)中的0.975 g(2.74 mmol)在步驟9.2中製備的產物置於氫化高壓釜中，且在惰性氛圍下添加0.14 g 10%鈀/木炭。在室溫下，在3巴之氫氣壓力下攪拌混合物4小時。在經由薄玻璃纖維紙過濾且在減壓下蒸發之後，獲得0.88 g呈紫色固體狀之預期產物，其按原樣用於下一步中。產率=99%。0.975 g (2.74 mmol) of the product prepared in step 9.2 in 55 mL of ethyl acetate/ethanol mixture (v/v = 1/1) was placed in a hydrogenation autoclave and 0.14 g of 10 was added under an inert atmosphere. % palladium / charcoal. The mixture was stirred at room temperature for 4 hours under a hydrogen pressure of 3 bar. After filtration through thin glass fiber paper and evaporation under reduced pressure, 0.88 g of the desired product as a purple solid was obtained, which was used in the next step. Yield = 99%.

10.4：4-[4-(7-胺基-6-胺甲醯基-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-2-基胺基)-3-氟-5-甲氧基苯基]哌嗪-1-甲酸第三丁酯10.4: 4-[4-(7-Amino-6-aminocarbamido-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-2-yl Amino)-3-fluoro-5-methoxyphenyl]piperazine-1-carboxylic acid tert-butyl ester

將0.36 g(1.35 mmol)在步驟2.6中製備的產物與0.88 g(2.70 mmol)在步驟10.3中製備的產物於3 mL NMP中之混合物置於圓底燒瓶中。在100℃下加熱懸浮液5.5小時。添加50 mL水及接著添加5 mL NaHCO3 飽和水溶液且藉由抽吸排乾所形成之沈澱物並在烘箱中乾燥。藉由矽膠管柱層析，以二氯甲烷/甲醇梯度(100/0至96/4)溶離來純化粗固體。獲得0.149 g呈紫色固體狀之預期產物。產率=20%。0.36 g (1.35 mmol) of the product prepared in step 2.6 was placed in a round bottom flask with a mixture of 0.88 g (2.70 mmol) of the product obtained in step 10.3 in 3 mL of NMP. The suspension was heated at 100 ° C for 5.5 hours. 50 mL of water was added followed by 5 mL of a saturated aqueous solution of NaHCO 3 and the precipitate formed by suction was drained and dried in an oven. The crude solid was purified by hydrazine gel column chromatography eluting with dichloromethane/methanol gradient (100/0 to 96/4). 0.149 g of the expected product was obtained as a purple solid. Yield = 20%.

10.5：7-胺基-8-乙基-2-(2-氟-6-甲氧基-4-哌嗪-1-基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽10.5: 7-Amino-8-ethyl-2-(2-fluoro-6-methoxy-4-piperazin-1-ylphenylamino)-5-keto-5,8-dihydro Pyrido[2,3-d]pyrimidin-6-carboxamide hydrochloride

將0.14 g(0.23 mmol)在步驟10.4中製備的產物懸浮於4 mL甲醇中，且添加1.15 mL(4.61 mmol)4N氯化氫之二噁烷溶液。在室溫下攪拌混合物隔夜，且添加***。藉由抽吸排乾固體，以戊烷沖洗並在烘箱中乾燥。獲得0.10 g呈灰色粉末狀之預期產物，其按原樣用於下一步中。產率(二鹽酸鹽)=95%。0.14 g (0.23 mmol) of the product prepared in step 10.4 was suspended in 4 mL of methanol, and 1.15 mL (4.61 mmol) of 4N hydrogen chloride in dioxane was added. The mixture was stirred at room temperature overnight and diethyl ether was added. The solid was drained by suction, rinsed with pentane and dried in an oven. 0.10 g of the expected product as a gray powder was obtained which was used in the next step. Yield (dihydrochloride) = 95%.

10.6：7-胺基-8-乙基-2-[4-(4-乙基哌嗪-1-基)-2-氟-6-甲氧基苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺10.6: 7-Amino-8-ethyl-2-[4-(4-ethylpiperazin-1-yl)-2-fluoro-6-methoxyphenylamino]-5-one- 5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide

將0.1 g(0.23 mmol)在步驟10.5中製備的鹽酸鹽懸浮於3 mL 1,2-二氯乙烷中，且逐份添加0.13 mL(0.72 mmol)二異丙基乙胺、0.04 mL(1.2 mmol)乙醛及接著添加0.10 g(0.48 mmol)三乙醯氧基硼氫化鈉。攪拌混合物2小時，且傾入0.25 N氫氧化鈉溶液中並添加二氯甲烷。在藉由沈降分離各相之後，以二氯甲烷萃取水相且合併有機相，經Na2 SO4 乾燥，過濾且在真空下濃縮。回收淡棕色固體，藉由矽膠管柱層析，以二氯甲烷/甲醇梯度(95/5至90/10)溶離來純化其。獲得0.085 g呈玻璃質黃色固體狀之預期產物。產率=73%。0.1 g (0.23 mmol) of the hydrochloride salt prepared in step 10.5 was suspended in 3 mL of 1,2-dichloroethane, and 0.13 mL (0.72 mmol) of diisopropylethylamine (0.04 mL) was added portionwise ( 1.2 mmol) acetaldehyde followed by 0.10 g (0.48 mmol) of sodium triethoxy hydride borohydride. The mixture was stirred for 2 hours and poured into a 0.25 N sodium hydroxide solution and dichloromethane was added. After the phases were separated by settling, the aqueous phase was extracted with dichloromethane and the combined organic phases were dried over Na 2 SO 4, filtered and concentrated in vacuo. The light brown solid was recovered, purified by EtOAc EtOAc EtOAc (EtOAc) Obtained 0.085 g of the expected product as a glassy yellow solid. Yield = 73%.

10.7：7-胺基-8-乙基-2-[4-(4-乙基哌嗪-1-基)-2-氟-6-甲氧基苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽10.7:7-Amino-8-ethyl-2-[4-(4-ethylpiperazin-1-yl)-2-fluoro-6-methoxyphenylamino]-5-one- 5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide hydrochloride

向0.08 g(0.18 mmol)在步驟10.6中製備的產物於5 mL甲醇中之溶液中添加0.53 mL(0.53 mmol)1.0 M氫氯醚。在室溫下攪拌混合物30分鐘且接著以***稀釋。藉由抽吸排乾沈澱物，以***及戊烷沖洗並在真空下乾燥。獲得0.133 g呈米色固體狀之預期產物。產率(二鹽酸鹽)=77%。m.p.>260℃。M+H+=485。To a solution of 0.08 g (0.18 mmol) of the product obtained in step 10.6 in 5 mL of methanol was added 0.53 mL (0.53 mmol) of 1.0 M Hydrochloroether. The mixture was stirred at room temperature for 30 minutes and then diluted with diethyl ether. The precipitate was drained by suction, rinsed with diethyl ether and pentane and dried under vacuum. 0.133 g of the expected product was obtained as a beige solid. Yield (dihydrochloride) = 77%. M.p.>260 °C. M+H+=485.

1 H NMR(DMSO-d6 ,400 MHz):δ11.8(寬s,1H);11.0(寬s,1H),9.1(寬s,1H);8.9(寬s,1H);8.0(寬s,1H),6.8-7.4(極寬s,<1H);6.45(d,1H);6.4(s,1H);3.5-4.4(s+m,9H);3.0-3.3(m,6H);1.3(t,3H);1.0-1.3(m,3H)。 1 H NMR (DMSO-d 6 , 400 MHz): δ 11.8 (width s, 1H); 11.0 (width s, 1H), 9.1 (width s, 1H); 8.9 (width s, 1H); s, 1H), 6.8-7.4 (extremely wide s, <1H); 6.45 (d, 1H); 6.4 (s, 1H); 3.5-4.4 (s+m, 9H); 3.0-3.3 (m, 6H) ; 1.3 (t, 3H); 1.0-1.3 (m, 3H).

實例11：7-胺基-8-(3-胺基丙基)-2-(4-嗎啉-4-基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽Example 11: 7-Amino-8-(3-aminopropyl)-2-(4-morpholin-4-ylphenylamino)-5-one-5,8-dihydropyridin[ 2,3-d]pyrimidine-6-methanamine hydrochloride

11.1：4-(3-第三丁氧羰基胺基丙基胺基)-2-氯嘧啶-5-甲酸11.1: 4-(3-Tertiaryoxycarbonylaminopropylamino)-2-chloropyrimidine-5-carboxylic acid

將2.21 g(11.45 mmol)在步驟2.3中製備的2,4-二氯-5-嘧啶甲酸(方法B)於20 mL無水THF中之溶液於冰浴上冷卻至2-5℃。隨後逐滴添加4.79 mL(34.35 mmol)三乙胺及2 g(11.48 mmol)(3-胺基丙基)胺基甲酸第三丁酯於15 mL無水THF中之溶液。在室溫下攪拌反應混合物30分鐘。添加乙酸乙酯且以1 N HCl水溶液及水洗滌有機相。合併有機相，經硫酸鈉乾燥，過濾且在真空下濃縮。獲得3.35 g呈黃色固體狀之預期產物。產率=88.6%。2.21 g (11.45 mmol) of the 2,4-dichloro-5-pyrimidinecarboxylic acid (Method B) prepared in Step 2.3 in 20 mL of dry THF was cooled to 2-5 ° C. Then a solution of 4.79 mL (34.35 mmol) of triethylamine and 2 g (11.48 mmol) of (3-aminopropyl)carbamic acid tert-butyl ester in 15 mL of dry THF was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes. Ethyl acetate was added and the organic phase was washed with 1 N aqueous HCl and water. The combined organics were dried with sodium sulfate, filtered and evaporated. 3.35 g of the expected product are obtained as a yellow solid. Yield = 88.6%.

11.2：[3-(2-氯-5-氟羰基嘧啶-4-基胺基)-丙基]胺基甲酸第三丁酯11.2: [3-(2-Chloro-5-fluorocarbonylpyrimidin-4-ylamino)-propyl]carbamic acid tert-butyl ester

向4.91 g(14.85 mmol)在步驟11.1中製備的產物於75 mL二氯甲烷中之懸浮液中添加2.07 g(14.85 mmol)三乙胺及接著添加1.88 mL(22.28 mmol)三聚氟化氰。在室溫下攪拌混合物2小時且以100 mL二氯甲烷稀釋溶液。以100 mL冰冷的NaHCO3 水溶液洗滌有機相三次，經MgSO4 乾燥，過濾且在真空下濃縮。獲得4.56 g預期產物，且其直接用於下一步中。產率=98%。To a suspension of 4.91 g (14.85 mmol) of the product prepared in step 11.1 in 75 mL dichloromethane was added 2.07 g (14.85 mmol) of triethylamine and then 1.88 mL (22.28 mmol). The mixture was stirred at room temperature for 2 hours and the solution was diluted with 100 mL of dichloromethane. In the organic phase three times with 100 mL NaHCO 3 aqueous solution was washed with ice-cooling, dried over MgSO 4, filtered and concentrated under vacuo. 4.56 g of the expected product was obtained and used directly in the next step. Yield = 98%.

11.3：[3-(7-胺基-6-胺甲醯基-2-氯-5-酮基-5H-吡啶并[2，3-d]嘧啶-8-基)丙基]胺基甲酸第三丁酯11.3: [3-(7-Amino-6-aminoformamido-2-chloro-5-keto-5H-pyrido[2,3-d]pyrimidin-8-yl)propyl]aminocarboxylic acid Third butyl ester

向已於冰浴上冷卻至2-5℃的1.21 g(14.39 mmol)氰基乙醯胺在20 mL無水DMF中的溶液中逐份添加1.73 g(43.17 mmol)60%氫化鈉。在2-5℃下攪拌混合物15分鐘，且隨後將此懸浮液快速添加至已於冰浴上預冷卻至2-5℃的4.56 g(13.70 mmol)在步驟11.2中製備的酸氟化物於30 mL無水DMF中之溶液中。在室溫下攪拌混合物隔夜且接著冷卻至2-5℃，且再添加0.22 g 60%氫化鈉。在室溫下攪拌介質隔夜，且隨後緩慢添加冰以破壞過量氫化物，且將反應混合物傾入冰水混合物中。藉由添加1 N HCl水溶液酸化所得混合物。藉由過濾分離所形成之沈澱物，以水沖洗且接著乾燥。獲得呈橙色固體狀之預期產物，其按原樣用於下一步中。產率=64%。1.73 g (43.17 mmol) of 60% sodium hydride was added portionwise to a solution of 1.21 g (14.39 mmol) of cyanoacetamide which had been cooled to 2-5 ° C on ice. The mixture was stirred at 2-5 ° C for 15 minutes, and then this suspension was quickly added to 4.56 g (13.70 mmol) of the acid fluoride prepared in step 11.2, which had been precooled to 2-5 ° C on an ice bath. In a solution of mL anhydrous DMF. The mixture was stirred overnight at room temperature and then cooled to 2-5 ° C, and an additional 0.22 g of 60% sodium hydride was added. The medium was stirred overnight at room temperature, and then ice was slowly added to destroy excess hydride, and the reaction mixture was poured into an ice water mixture. The resulting mixture was acidified by the addition of 1 N aqueous HCl. The precipitate formed was separated by filtration, rinsed with water and then dried. The expected product was obtained as an orange solid which was used in the next step. Yield = 64%.

11.4：{3-[7-胺基-6-胺甲醯基-2-(4-嗎啉-4-基苯基胺基)-5-酮基-5H-吡啶并[2,3-d]嘧啶-8-基]丙基}胺基甲酸第三丁酯11.4: {3-[7-Amino-6-amine-mercapto-2-(4-morpholin-4-ylphenylamino)-5-one-5H-pyrido[2,3-d Pyrimidin-8-yl]propyl}aminocarboxylic acid tert-butyl ester

將0.60 g(1.51 mmol)在步驟11.3中製備的產物與0.53 g(3.02 mmol)4-嗎啉-4-基苯胺於6.5 mL NMP中之混合物置於10 mL微波管中。將經密封之管置於微波烘箱(CEM machine，型號Discovery)中且將混合物在120℃下，在壓力下在75 W之功率下加熱60分鐘，且接著冷卻至室溫。添加15 mL水及接著添加5 mL NaHCO3 飽和水溶液，且藉由抽吸排乾所形成之沈澱物並接著在烘箱中乾燥。在甲醇中濕磨粗固體，藉由抽吸排乾且在烘箱中在真空下乾燥。獲得0.159 g呈固體狀之預期產物。產率=20%。A mixture of 0.60 g (1.51 mmol) of the product prepared in step 11.3 and 0.53 g (3.02 mmol) of 4-morpholin-4-ylaniline in 6.5 mL of NMP was placed in a 10 mL microwave tube. The sealed tube was placed in a microwave oven (CEM machine, Model Discovery) and the mixture was heated at 120 ° C under pressure at 75 W for 60 minutes and then cooled to room temperature. 15 mL of water was added followed by 5 mL of a saturated aqueous solution of NaHCO 3 and the precipitate formed was drained by suction and then dried in an oven. The crude solid was wet milled in methanol, drained by suction and dried under vacuum in an oven. 0.159 g of the expected product was obtained as a solid. Yield = 20%.

11.5：7-胺基-8-(3-胺基丙基)-2-(4-嗎啉-4-基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽11.5: 7-Amino-8-(3-aminopropyl)-2-(4-morpholin-4-ylphenylamino)-5-one-5-8-dihydropyrido[2 ,3-d]pyrimidine-6-formamide hydrochloride

將0.16 g(0.30 mmol)在步驟11.4中製備的產物懸浮於4 mL無水二噁烷中，且添加0.74 mL(2.95 mmol)氯化氫於二噁烷中之4 N溶液。在室溫下攪拌混合物5小時，且添加***。藉由抽吸排乾固體，以戊烷沖洗並在烘箱中乾燥。獲得0.14 g呈白色粉末狀之預期產物。產率(二鹽酸鹽)=定量。m.p.=250℃。M+H+ =439。0.16 g (0.30 mmol) of the product prepared in step 11.4 was suspended in 4 mL of dry dioxane, and 0.74 mL (2.95 mmol) of 4 N solution of hydrogen chloride in dioxane was added. The mixture was stirred at room temperature for 5 hours, and diethyl ether was added. The solid was drained by suction, rinsed with pentane and dried in an oven. 0.14 g of the expected product was obtained as a white powder. Yield (dihydrochloride) = quantitative. Mp = 250 °C. M+H + = 439.

1 H NMR(DMSO-d6 ,400 MHz):δ11.9(寬s,1H);10.2-10.4(極寬s,<1H);10.2(s,1H);9.0(s,1H);8.4(寬s,1H);8.2(d,2H);7.7(d,2H);7.4(寬s,1H);7.1-7.5(極寬s,<1H);4.4(m,2H);3.9(m,4H);3.3(m,4H);2.9(m,2H);2.1(m,2H)。 1 H NMR (DMSO-d 6 , 400 MHz): δ 11.9 (width s, 1H); 10.2-10.4 (ext. s, <1H); 10.2 (s, 1H); 9.0 (s, 1H); (width s, 1H); 8.2 (d, 2H); 7.7 (d, 2H); 7.4 (width s, 1H); 7.1-7.5 (extreme width s, <1H); 4.4 (m, 2H); m, 4H); 3.3 (m, 4H); 2.9 (m, 2H); 2.1 (m, 2H).

實例12：7-胺基-8-乙基-2-[4-(2-羥基乙基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺Example 12: 7-Amino-8-ethyl-2-[4-(2-hydroxyethyl)phenylamino]-5-one-5,8-dihydropyrido[2,3-d Pyrimidine-6-formamide

將2.1 g(7.89 mmol)在步驟2.6中製備的產物與2.17 g(15.79 mmol)2-(4-胺基苯基)乙醇於10 mL NMP中之混合物在100℃下於密封管中加熱3小時。將熱的反應混合物傾入125 mL水與25 mL NaHCO3 飽和水溶液之混合物中。藉由抽吸排乾所形成之沈澱物，以水沖洗且接著在烘箱中在真空下乾燥。在***中濕磨之後，獲得2.5 g呈淡棕色固體狀之預期產物。產率=89.2%。A mixture of 2.1 g (7.89 mmol) of the product prepared in step 2.6 and 2.17 g (15.79 mmol) of 2-(4-aminophenyl)ethanol in 10 mL of NMP was heated at 100 ° C for 3 hours in a sealed tube. . The hot reaction mixture was poured into a mixture of water and 25 mL of a saturated aqueous solution of NaHCO 3 125 mL. The precipitate formed by draining was rinsed with water and then dried under vacuum in an oven. After wet milling in diethyl ether, 2.5 g of the desired product was obtained as pale brown solid. Yield = 89.2%.

藉由在最少量甲醇中濕磨0.2 g先前固體，藉由抽吸排乾，以***沖洗且用真空泵乾燥來獲得分析上純的樣品。由此回收0.15 g呈米色粉末狀之純預期產物。An analytically pure sample was obtained by wet grinding 0.2 g of the previous solid in a minimum amount of methanol, draining by suction, rinsing with diethyl ether and drying with a vacuum pump. 0.15 g of the pure expected product in the form of a beige powder was thus recovered.

m.p.=289℃。M+H+ =369。Mp = 289 ° C. M+H + = 369.

1 H NMR(DMSO-d6;400 MHz):δ11.8(寬s,1H);10.4(d,1H);10.1(寬s,1H);9.0(s,1H);8.0(寬s,1H);7.7(d,2H);7.2(d,2H);4.6(t,1H);4.4(m,2H);3.6(m,2H),2.7(m,2H);1.3(t,3H)。 1 H NMR (DMSO-d6; 400 MHz): δ 11.8 (width s, 1H); 10.4 (d, 1H); 10.1 (width s, 1H); 9.0 (s, 1H); 8.0 (width s, 1H) 7.7(d,2H);7.2(d,2H);4.6(t,1H);4.4(m,2H);3.6(m,2H),2.7(m,2H);1.3(t,3H) .

實例13：7-胺基-8-乙基-5-酮基-2-[4-(2-哌啶-1-基乙基)苯基胺基]-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽Example 13: 7-Amino-8-ethyl-5-keto-2-[4-(2-piperidin-1-ylethyl)phenylamino]-5,8-dihydropyridin[ 2,3-d]pyrimidine-6-methanamine hydrochloride

13.1：2-[4-(7-胺基-6-胺甲醯基-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-2-基胺基)苯基]甲烷磺酸乙酯13.1: 2-[4-(7-Amino-6-aminocarbamido-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-2-yl Ethyl)phenyl]methanesulfonate

向已於冰水浴上冷卻至2-5℃的1.0 g(2.71 mmol)實例12之產物於50 mL四氫呋喃中之懸浮液中添加1.51 mL(10.86 mmol)三乙胺，接著逐滴添加0.84 mL(10.86 mmol)甲烷磺醯氯。在50℃下加熱反應混合物2小時。將其傾入水中且添加乙酸乙酯。以0.5 N HCl水溶液及NaCl飽和水溶液洗滌有機相且接著經Na2 SO4 乾燥，過濾並在真空下濃縮。獲得0.94 g呈棕色固體狀之預期產物，其純度足以執行下一步驟。1.51 mL (10.86 mmol) of triethylamine was added to a suspension of 1.0 g (2.71 mmol) of the product of Example 12 in 50 mL of tetrahydrofuran, which was cooled to 2-5 ° C in an ice water bath, followed by dropwise addition of 0.84 mL ( 10.86 mmol) methane sulfonium chloride. The reaction mixture was heated at 50 ° C for 2 hours. It was poured into water and ethyl acetate was added. To 0.5 N HCl aqueous solution and the organic phase was washed with saturated NaCl and then dried over Na 2 SO 4, filtered and concentrated in vacuo. 0.94 g of the expected product was obtained as a brown solid, which was pure enough to carry out the next step.

13.2：7-胺基-8-乙基-5-酮基-2-[4-(2-哌啶-1-基乙基)苯基胺基]-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽13.2: 7-Amino-8-ethyl-5-keto-2-[4-(2-piperidin-1-ylethyl)phenylamino]-5,8-dihydropyrido[2 ,3-d]pyrimidine-6-formamide hydrochloride

將1.1 g(2.46 mmol)在步驟13.1中製備的產物及1.17 mL(11.83 mmol)哌啶置於圓底燒瓶中。在60℃下加熱混合物2小時且接著濃縮。藉由矽膠管柱層析，以二氯甲烷/甲醇梯度(100/0至90/10)溶離來純化殘餘物。獲得0.12 g(0.28 mmol)呈鹼形式之預期產物，藉由以0.55 mL(0.55 mmol)於甲醇中之1 M氫氯醚處理來使其成鹽。m.p.=216℃。M+H+ =436。1.1 g (2.46 mmol) of the product prepared in step 13.1 and 1.17 mL (11.83 mmol) of piperidine were placed in a round bottom flask. The mixture was heated at 60 ° C for 2 hours and then concentrated. The residue was purified by hydrazine gel column chromatography eluting with dichloromethane/methanol gradient (100/0 to 90/10). 0.12 g (0.28 mmol) of the expected product was obtained as a base, which was crystallized by treatment with 0.55 mL (0.55 mmol) of 1M hydrochloroether in methanol. Mp = 216 °C. M+H + =436.

1 H NMR(DMSO-d6 ,400 MHz):δ11.8(寬s,1H);10.4(寬s,~1H);10.2(s,1H);9.0(s,1H);8.1(寬s,1H);7.7(d,2H);7.1-7.3(極寬s,<1H);4.4(q,2H);3.5(m,2H);3.2(m,2H);3.1(m,2H);2.9(m,2H);1.7-1.9(m,5H);1.4(m,1H),1.3(t,3H) 1 H NMR (DMSO-d 6 , 400 MHz): δ 11.8 (width s, 1H); 10.4 (width s, ~1H); 10.2 (s, 1H); 9.0 (s, 1H); 8.1 (width s , 1H); 7.7 (d, 2H); 7.1-7.3 (extremely wide s, <1H); 4.4 (q, 2H); 3.5 (m, 2H); 3.2 (m, 2H); 3.1 (m, 2H) ;2.9(m,2H);1.7-1.9(m,5H);1.4(m,1H),1.3(t,3H)

實例14：7-胺基-2-[4-(4-環丙基哌嗪-1-基)-2-二氟甲氧基苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽Example 14: 7-Amino-2-[4-(4-cyclopropylpiperazin-1-yl)-2-difluoromethoxyphenylamino]-8-ethyl-5-one- 5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide hydrochloride

14.1：2-二氟甲氧基-4-氟-1-硝基苯14.1: 2-Difluoromethoxy-4-fluoro-1-nitrobenzene

向3.14 g(20.0 mmol)5-氟-2-硝基苯酚於36 mL DMF中之溶液中添加6.1 g(40.0 mmol)氯二氟乙酸鈉及3.31 g(24.0 mmol)粉末狀碳酸鈉。在100℃下加熱反應混合物4小時30分鐘且隨後使其冷卻至室溫。添加4 N HCl水溶液且在室溫下攪拌混合物2小時。以100 mL水及100 mL***稀釋所得混合物。以***萃取水相且隨後合併有機相，以1 N NaOH水溶液及接著以NaCl飽和水溶液洗滌，經Na2 sO4 乾燥，過濾並在真空下濃縮。獲得3.68 g呈黃色油狀之預期產物，其按原樣用於下一步中。產率=89%。To a solution of 3.14 g (20.0 mmol) of 5-fluoro-2-nitrophenol in 36 mL of DMF was added 6.1 g (40.0 mmol) of sodium chlorodifluoroacetate and 3.31 g (24.0 mmol) of powdered sodium carbonate. The reaction mixture was heated at 100 ° C for 4 hours and 30 minutes and then allowed to cool to room temperature. A 4 N aqueous HCl solution was added and the mixture was stirred at room temperature for 2 hr. The resulting mixture was diluted with 100 mL of water and 100 mL of diethyl ether. Aqueous phase was extracted with diethyl ether and then the combined organic phase, and then with saturated aqueous NaCl aq 1 N NaOH, dried over Na 2 sO 4, filtered and concentrated in vacuo. 3.68 g of the expected product as a yellow oil was obtained which was used in the next step. Yield = 89%.

14.2：1-環丙基-4-(3-二氟甲氧基-4-硝基苯基)哌嗪14.2: 1-Cyclopropyl-4-(3-difluoromethoxy-4-nitrophenyl)piperazine

向於30 mL乙腈中的2.07 g(10.0 mmol)在步驟14.1中製備的產物中添加5.99 mL(35.0 mmol)二異丙基乙胺及接著添加2.09 g(10.5 mmol)細粉狀N-環丙基哌嗪(supplier)。在100℃下加熱反應混合物1小時30分鐘，冷卻並在真空下濃縮。將殘餘物溶解於75 mL乙酸乙酯中且以NaHCO3 飽和水溶液及NaCl飽和水溶液洗滌。經Na2 sO4 乾燥有機相，過濾且在真空下濃縮。在環己烷中濕磨之後，藉由抽吸排乾固體並在烘箱中在真空下乾燥。獲得2.33 g呈黃色固體狀之預期產物，其按原樣用於下一步中。產率=74.5%。To 2.07 g (10.0 mmol) of 30 mL of acetonitrile, 5.99 mL (35.0 mmol) of diisopropylethylamine and 2.09 g (10.5 mmol) of fine powdery N-cyclopropane were added to the product prepared in step 14.1. Piperazine (supplier). The reaction mixture was heated at 100 ° C for 1 hour and 30 minutes, cooled and concentrated under vacuum. The residue was dissolved in 75 mL of ethyl acetate and washed with saturated aqueous NaHCO 3 and saturated aqueous NaCl. Dried over Na 2 sO 4 organic phase was filtered and concentrated in vacuo. After wet milling in cyclohexane, the solids were drained by suction and dried under vacuum in an oven. 2.33 g of the expected product as a yellow solid was obtained which was used in the next step. Yield = 74.5%.

14.34-(4-環丙基哌嗪-1-基)-2-二氟甲氧基苯胺14.34-(4-Cyclopropylpiperazin-1-yl)-2-difluoromethoxyaniline

將於50 mL乙酸乙酯/乙醇混合物(v/v=1/1)中的2.32 g(7.4 mmol)在步驟14.2中製備的產物置於氫化高壓釜中，且在惰性氛圍下添加0.196 g 10%鈀/木炭。在室溫下，在2.5巴之氫氣壓力下攪拌混合物1小時45分鐘。在經由薄玻璃纖維紙過濾且在減壓下蒸發之後，獲得2.09 g呈米色固體狀之預期產物，其按原樣用於下一步中。定量產率。2.32 g (7.4 mmol) of the product prepared in step 14.2 in 50 mL of ethyl acetate/ethanol mixture (v/v = 1/1) was placed in a hydrogenation autoclave and 0.196 g of 10 was added under an inert atmosphere. % palladium / charcoal. The mixture was stirred at a hydrogen pressure of 2.5 bar for 1 hour and 45 minutes at room temperature. After filtration through a thin glass fiber paper and evaporation under reduced pressure, 2.09 g of the desired product as a beige solid was obtained, which was used in the next step. Quantitative yield.

14.4：7-胺基-2-[4-(4-環丙基哌嗪-1-基)-2-二氟甲氧基苯基胺基]-8-乙基-5-酮基-5 ,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺 14.4:7-Amino-2-[4-(4-cyclopropylpiperazin-1-yl)-2-difluoromethoxyphenylamino]-8-ethyl-5-one-5 , 8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide

將0.44 g(1.65 mmol)在步驟2.6中製備的產物與0.93 g(3.3 mmol)在步驟14.3中製備的產物於3 mL NMP中之混合物置於圓底燒瓶中。在100℃下加熱溶液18小時。添加50 mL水及接著添加5 mL NaHCO3 飽和水溶液且藉由抽吸排乾所形成之沈澱物並接著在烘箱中乾燥。藉由矽膠管柱層析，以二氯甲烷/甲醇梯度(100/0至90/10)溶離來純化粗固體。最終獲得0.117 g呈黃色固體狀之預期產物。產率=12%。A mixture of 0.44 g (1.65 mmol) of the product prepared in step 2.6 and 0.93 g (3.3 mmol) of the product obtained in step 14.3 in 3 mL of NMP was placed in a round bottom flask. The solution was heated at 100 ° C for 18 hours. 50 mL of water was added followed by 5 mL of a saturated aqueous solution of NaHCO 3 and the precipitate formed by suction was drained and then dried in an oven. The crude solid was purified by hydrazine gel column chromatography eluting with dichloromethane/methanol gradient (100/0 to 90/10). Finally, 0.117 g of the expected product was obtained as a yellow solid. Yield = 12%.

14.5：7-胺基-2-[4-(4-環丙基哌嗪-1-基)-2-二氟甲氧基苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽14.5:7-Amino-2-[4-(4-cyclopropylpiperazin-1-yl)-2-difluoromethoxyphenylamino]-8-ethyl-5-one-5 , 8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide hydrochloride

將0.11 g(0.21 mmol)在步驟14.4中製備的產物懸浮於3 mL無水二噁烷中且添加0.63 mL(0.63 mmol)氯化氫於***中之1 M溶液。以***稀釋混合物且隨後藉由抽吸排乾固體，以戊烷沖洗並在烘箱中乾燥。獲得0.11 g呈黃色粉末狀之預期產物。產率(二鹽酸鹽)=87%。m.p.=204-206℃。M+H+ =515。0.11 g (0.21 mmol) of the product prepared in step 14.4 was suspended in 3 mL anhydrous dioxane and a solution of 0.63 mL (0.63 mmol) of hydrogen chloride in diethyl ether. The mixture was diluted with ether and then the solid was drained by suction, rinsed with pentane and dried in oven. 0.11 g of the expected product was obtained as a yellow powder. Yield (dihydrochloride) = 87%. Mp=204-206 °C. M+H + = 515.

1 H NMR(DMSO-d6 ,400 MHz):δ11.8(寬s,1H);11.0(寬s,1H);10.1-10.6(極寬s,<1H);9.2(s,1H);8.9(s,1H);8.0(寬s,1H);7.6(d,2H);7.1(t,1H);7.0(d,1H);6.9(s,1H);4.3(m,2H);3.9(m,2H);3.6(m,2H);3.4(m,2H);3.2(m,2H);3.0(m,1H);1.1-1.3(m,5H);0.8(m,2H)。 1 H NMR (DMSO-d 6 , 400 MHz): δ 11.8 (width s, 1H); 11.0 (width s, 1H); 10.1 - 10.6 (ext. s, <1H); 9.2 (s, 1H); 8.9 (s, 1H); 8.0 (width s, 1H); 7.6 (d, 2H); 7.1 (t, 1H); 7.0 (d, 1H); 6.9 (s, 1H); 4.3 (m, 2H); 3.9 (m, 2H); 3.6 (m, 2H); 3.4 (m, 2H); 3.2 (m, 2H); 3.0 (m, 1H); 1.1-1.3 (m, 5H); 0.8 (m, 2H) .

實例15：(±)-7-胺基-2-[4-(反-2-二甲基胺基環丙基)苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽Example 15: (±)-7-Amino-2-[4-(trans-2-dimethylaminocyclopropyl)phenylamino]-8-ethyl-5-one-5,8 -dihydropyrido[2,3-d]pyrimidin-6-carboxamide hydrochloride

15.1：( ±)-反-2-(4-硝基苯基)環丙烷甲酸 15.1: ( ± ) -Trans -2-(4-nitrophenyl)cyclopropanecarboxylic acid

將20.3 g(125.0 mmol)(±)-反-2-苯基-環丙烷甲酸(Aldrich)逐份添加至150 mL 70%濃硝酸溶液中。在室溫下攪拌混合物2小時，且觀察到在反應介質中形成白色細粉。將混合物冷卻至10℃，且藉由抽吸排乾固體，以40 mL水沖洗四次且接著在烘箱中乾燥。將固體在160℃下部分溶解於700 mL二甲苯中且使其冷卻至室溫。藉由抽吸排乾固體，以二甲苯及接著以戊烷沖洗並在烘箱中在真空下乾燥。獲得12.6 g含有預期產物與鄰-硝基區位異構物之90/10混合物的灰白色固體。混合物按原樣用於下一步中。產率=48%。20.3 g (125.0 mmol) of (±)-trans-2-phenyl-cyclopropanecarboxylic acid (Aldrich) was added portionwise to 150 mL of a 70% concentrated nitric acid solution. The mixture was stirred at room temperature for 2 hours, and a white fine powder was observed to formed in the reaction medium. The mixture was cooled to 10 ° C, and the solid was drained by suction, washed four times with 40 mL of water and then dried in an oven. The solid was partially dissolved in 700 mL of xylene at 160 ° C and allowed to cool to room temperature. The solid was drained by suction, rinsed with xylene and then with pentane and dried in vacuo in an oven. 12.6 g of an off-white solid containing a 90/10 mixture of the desired product and the o-nitro-s. The mixture was used as it is in the next step. Yield = 48%.

15.2：( ±)-[反-2-(4-硝基苯基)環丙基]胺基甲酸第三丁酯 15.2: ( ± )-[trans-2-(4-nitrophenyl)cyclopropyl]carbamic acid tert-butyl ester

向12.4 g(60.0 mmol)在步驟15.1中製備的混合物於150 mL第三丁醇中之懸浮液中添加9.2 mL(66.0 mmol)Et3 N，接著逐滴添加14.2 mL(66 mmol)二苯基磷醯基疊氮化物。在95℃下加熱反應混合物4小時30分鐘且接著使其冷卻至室溫。以300 mL乙酸乙酯稀釋所得混合物且以150 mL NaHCO3 飽和水溶液及接著以NaCl飽和水溶液洗滌有機相。在蒸發之後，將固體殘餘物溶解於50 mL乙酸乙酯及100 mL環己烷中，且加熱直至溶解完全。將溶液冷卻至室溫，且藉由抽吸排乾沈澱物，以環己烷及戊烷沖洗。粉色固體幾乎完全溶解於150 mL CH2 Cl2 中且接著經由矽膠過濾，以CH2 Cl2 ，接著以二氯甲烷/乙酸乙酯混合物(1/4)溶離。蒸發濾液得到7.12 g呈淡棕色固體狀之預期產物。產率=42.5%。The mixture prepared in step 15.1 was added 9.2 mL (66.0 mmol) Et 3 N in 150 mL of tertiary butanol To a suspension of 12.4 g (60.0 mmol), followed by dropwise adding 14.2 mL (66 mmol) diphenyl Phosphonium azide. The reaction mixture was heated at 95 ° C for 4 hours and 30 minutes and then allowed to cool to room temperature. To 300 mL The resulting mixture was diluted with ethyl acetate and with 150 mL NaHCO 3 saturated solution and then washed with saturated aqueous NaCl organic phase. After evaporation, the solid residue was dissolved in 50 mL ethyl acetate and 100 mL cyclohexane and heated until dissolved. The solution was cooled to room temperature and the precipitate was drained by suction and rinsed with cyclohexane and pentane. Pink solid almost completely dissolved in 150 mL CH 2 Cl 2 and then filtered through silica gel in order to CH 2 Cl 2, followed by methylene chloride / ethyl acetate mixture (1/4) eluting. Evaporation of the filtrate gave 7.12 g of the desired product as a pale brown solid. Yield = 42.5%.

15.3：( ±)-[反-2-(4-胺基苯基)環丙基]胺基甲酸第三丁酯 15.3: ( ± )-[trans-2-(4-aminophenyl)cyclopropyl]carbamic acid tert-butyl ester

將1.39 g(5.0 mmol)步驟15.2中製備的產物溶解於25 mL熱乙酸乙酯中。在冷卻至室溫之後，連續添加25 mL絕對乙醇及0.057 g(0.25 mmol)氧化鉑(IV)。將反應混合物置於2.75巴之氫氣壓力下2小時，且經由薄玻璃纖維紙過濾。濾液在真空下濃縮，且藉由矽膠管柱層析，以環己烷/乙酸乙酯梯度(由70/30至55/45)溶離純化。獲得1.05 g預期產物。產率=85%。1.39 g (5.0 mmol) of the product prepared in step 15.2 was dissolved in 25 mL of hot ethyl acetate. After cooling to room temperature, 25 mL of absolute ethanol and 0.057 g (0.25 mmol) of platinum (IV) oxide were continuously added. The reaction mixture was placed under a hydrogen pressure of 2.75 bar for 2 hours and filtered through a thin glass fiber paper. The filtrate was concentrated in vacuo and purified by flash chromatography eluting with EtOAc/EtOAc (EtOAc:EtOAc 1.05 g of the expected product was obtained. Yield = 85%.

15.4：( ±)-{反-2-[4-(7-胺基-6-胺甲醯基-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-2-基胺基)苯基]環丙基}胺基甲酸第三丁酯 15.4: ( ± )-{trans-2-[4-(7-Amino-6-aminocarbazinyl-8-ethyl-5-keto-5,8-dihydropyrido[2,3- d]pyrimidin-2-ylamino)phenyl]cyclopropyl}aminocarboxylic acid tert-butyl ester

將0.87 g(3.5 mmol)步驟2.6中製備的產物與0.47 g(1.75 mmol)步驟15.3中製備的產物於3 mL NMP中之混合物置於圓底燒瓶中。溶液在100℃加熱18小時。添加50 mL水及接著添加5 mL NaHCO3 飽和水溶液，所形成之沈澱物藉由抽吸排乾並接著在烘箱中乾燥。粗固體藉由矽膠管柱層析，以二氯甲烷/甲醇梯度(98/2至92.5/7.5)溶離純化。最終獲得0.46 g呈橙色固體狀之預期產物。產率=55%。A mixture of 0.87 g (3.5 mmol) of the product prepared in Step 2.6 and 0.47 g (1.75 mmol) of the product from Step 15.3 in 3 mL of NMP was placed in a round bottom flask. The solution was heated at 100 ° C for 18 hours. 50 mL of water was added followed by 5 mL of a saturated aqueous solution of NaHCO 3 , and the resulting precipitate was drained by suction and then dried in an oven. The crude solid was purified by chromatography on a sep. column chromatography eluting with dichloromethane/methanol gradient (98/2 to 92.5 / 7.5). Finally, 0.46 g of the expected product was obtained as an orange solid. Yield = 55%.

15.5：( ±)-7-胺基-2-[4-(反-2-胺基環丙基)苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽 15.5: ( ± )-7-Amino-2-[4-(trans-2-aminocyclopropyl)phenylamino]-8-ethyl-5-one-5,8-dihydropyridine And [2,3-d]pyrimidine-6-methanamine hydrochloride

向0.46 g(0.96 mmol)步驟15.4中製備的產物於20 mL二氯甲烷/甲醇混合物(1/1)中的懸浮液中添加4.8 mL(19.2 mmol)4N氯化氫之二噁烷溶液。混合物在室溫攪拌5小時且接著以***稀釋，固體藉由抽吸排乾，以***沖洗，並在烘箱中在真空下乾燥。獲得0.48 g深紫色固體，其用於下一步驟中。產率(二鹽酸鹽)=定量。To a suspension of 0.46 g (0.96 mmol) of the product obtained in step 15.4 in 20 mL of dichloromethane / methanol mixture (1/1) was added 4.8 mL (19.2 mmol) of 4N hydrogen chloride in dioxane. The mixture was stirred at room temperature for 5 hours and then diluted with diethyl ether. The solid was dried with suction, rinsed with diethyl ether and dried in vacuo. 0.48 g of a dark purple solid was obtained which was used in the next step. Yield (dihydrochloride) = quantitative.

15.6：(±)-7-胺基-2-[4-(反-2-二甲基胺基環丙基)苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺15.6: (±)-7-Amino-2-[4-(trans-2-dimethylaminocyclopropyl)phenylamino]-8-ethyl-5-keto-5,8- Dihydropyrido[2,3-d]pyrimidine-6-carboxamide

向0.19 g(0.43 mmol)在步驟15.5中製備的產物於5.4 mL乙腈中的懸浮液中添加0.22 mL(1.29 mmol)二異丙基乙胺及0.64 mL(8.58 mmol)70%福馬林。攪拌3分鐘之後，添加0.13 g(2.14 mmol)氰基硼氫化鈉且在室溫下攪拌混合物3小時。濃縮反應混合物且接著溶解於6 mL水及3 mL 35%NaOH水溶液中。藉由抽吸排乾固體並在烘箱中在真空下乾燥。藉由矽膠管柱層析，以含有痕量濃NH4 OH水溶液之二氯甲烷/甲醇混合物(98/2至85/15)溶離來純化其。獲得0.054 g預期產物。產率=31%。To a suspension of 0.19 g (0.43 mmol) of the product obtained in step 15.5 in 5.4 mL of acetonitrile was added 0.22 mL (1.29 mmol) diisopropylethylamine and 0.64 mL (8.58 mmol) of 70%. After stirring for 3 minutes, 0.13 g (2.14 mmol) of sodium cyanoborohydride was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and then dissolved in 6 mL water and 3 mL aqueous 35% NaOH. The solid was drained by suction and dried under vacuum in an oven. By silica gel column chromatography, purified solvent containing traces from which concentrated NH 4 OH aqueous solution of methylene chloride / methanol mixture (98/2 to 85/15). 0.054 g of the expected product was obtained. Yield = 31%.

15.7：(±)-7-胺基-2-[4-(反-2-二甲基胺基環丙基)苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽15.7: (±)-7-Amino-2-[4-(trans-2-dimethylaminocyclopropyl)phenylamino]-8-ethyl-5-keto-5,8- Dihydropyrido[2,3-d]pyrimidin-6-carboxamide hydrochloride

向0.05 g(0.13 mmol)在步驟15.6中製備的產物於2.5 mL甲醇中之溶液中添加0.20 mL(0.4 mmol)2.0 M氫氯醚。在室溫下攪拌混合物5分鐘且接著蒸發至乾燥。藉由製備型HPLC純化殘餘物。將對應於預期純產物之溶離份蒸發至乾燥，接著溶解於甲醇中。添加***且藉由抽吸排乾固體並在烘箱中在真空下乾燥。獲得0.031 g預期產物。產率(二鹽酸鹽)=49%。m.p.=208-210℃(分解)。M+H+ =408。To a solution of 0.05 g (0.13 mmol) of the product obtained in step 15.6 in 2.5 mL of methanol was added 0.20 mL (0.4 mmol). The mixture was stirred at room temperature for 5 minutes and then evaporated to dryness. The residue was purified by preparative HPLC. The fraction corresponding to the expected pure product was evaporated to dryness and then dissolved in methanol. Diethyl ether was added and the solid was drained by suction and dried under vacuum in an oven. 0.031 g of the expected product was obtained. Yield (dihydrochloride) = 49%. Mp = 208-210 ° C (decomposition). M+H + = 408.

1 H NMR(DMSO-d6 ,400 MHz):δ11.8(寬s,1H);10.7(寬s,1H);10.1-10.4(極寬s,<1H);10.2(s,1H);9.0(s,1H);8.1(寬s,1H),7.7(d,1H);6.45(d,1H);7.2(d,1H);4.4(m,2H);3.1(m,1H);2.9(d,3H);2.85(d,3H);2.7(m,1H);1.7(m,1H);1,2-1.4(m+t,4H)。 1 H NMR (DMSO-d 6 , 400 MHz): δ 11.8 (width s, 1H); 10.7 (width s, 1H); 10.1 - 10.4 (ext. s, <1H); 10.2 (s, 1H); 9.0 (s, 1H); 8.1 (width s, 1H), 7.7 (d, 1H); 6.45 (d, 1H); 7.2 (d, 1H); 4.4 (m, 2H); 3.1 (m, 1H); 2.9 (d, 3H); 2.85 (d, 3H); 2.7 (m, 1H); 1.7 (m, 1H); 1,2-1.4 (m+t, 4H).

實例16：8-乙基-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-7-甲基胺基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽Example 16: 8-Ethyl-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]phenylamino}-7-A Amino-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide hydrochloride

16.1：4-(3-甲氧基-4-硝基苯基)-1,2,3,6-四氫吡啶鹽酸鹽16.1: 4-(3-Methoxy-4-nitrophenyl)-1,2,3,6-tetrahydropyridine hydrochloride

將10.0 g(29.91 mmol)在步驟4.2中製備的產物於120 mL二氯甲烷中之溶液於冰水浴上冷卻至2-5℃，且隨後經1小時緩慢添加60 mL HCl於二噁烷中之4 N溶液(Aldrich)。在室溫下攪拌反應混合物隔夜。藉由抽吸排乾所形成之固體，以***沖洗且接著在烘箱中乾燥。回收7.6 g呈米色固體狀之預期產物。產率=94%。10.0 g (29.91 mmol) of the product prepared in step 4.2 in 120 mL of dichloromethane was cooled to 2-5 ° C on an ice water bath, and then slowly added 60 mL HCl in dioxane over 1 hour. 4 N solution (Aldrich). The reaction mixture was stirred at room temperature overnight. The solid formed by draining was rinsed with diethyl ether and then dried in an oven. 7.6 g of the expected product was obtained as a beige solid. Yield = 94%.

16.2：4-(3-甲氧基-4-硝基苯基)-1-(3,3,3-三氟丙基)-1,2,3,6-四氫吡啶16.2: 4-(3-Methoxy-4-nitrophenyl)-1-(3,3,3-trifluoropropyl)-1,2,3,6-tetrahydropyridine

將6.6 g(24.38 mmol)在步驟16.1中製備的鹽酸鹽於110 mL二氯甲烷中之溶液在冰水浴中冷卻。逐份連續添加14 mL(243.8 mmol)冰醋酸、8.19 g(73.14 mmol)3,3,3-三氟丙醛及12.9 g(60.95 mmol)三乙醯氧基硼氫化鈉。在室溫下攪拌混合物3小時且接著以二氯甲烷、水及1 N NaOH水溶液稀釋。以二氯甲烷萃取水相且合併有機相，經Na2 SO4 乾燥，過濾且在真空下濃縮。回收8.4 g最主要含有預期產物之黃色油狀物，且其按原樣用於下一步中。定量粗產率。A solution of 6.6 g (24.38 mmol) of the hydrochloride salt prepared in step 16.1 in 110 mL of dichloromethane was cooled in ice water. 14 mL (243.8 mmol) of glacial acetic acid, 8.19 g (73.14 mmol) of 3,3,3-trifluoropropanal and 12.9 g (60.95 mmol) of sodium triethoxysulfonate were continuously added portionwise. The mixture was stirred at room temperature for 3 hours and then diluted with dichloromethane, water and 1 N aqueous NaOH. Aqueous phase was extracted with dichloromethane and the combined organic phases were dried over Na 2 SO 4, filtered and concentrated in vacuo. 8.4 g of the yellow oil, which most predominantly contained the expected product, was recovered and used as it is in the next. Quantitative crude yield.

16.3：2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯胺16.3: 2-Methoxy-4-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]aniline

將1.65 g(5.0 mmol)在步驟16.2中製備的產物置於氫化高壓釜中的120 mL乙醇/乙酸混合物(v/v=1/1)中，且在惰性氛圍下添加0.150 g氧化鉑(IV)。在室溫下，在4巴氫氣壓力下攪拌混合物4小時。在經由薄玻璃纖維紙過濾且在減壓下蒸發至乾燥之後，將油狀殘餘物溶解於氯仿中且以1N NaOH水溶液洗滌。經Na2 SO4 乾燥有機相，過濾且在真空下濃縮。獲得1.5 g呈棕色油狀之預期產物，其按原樣用於下一步中。粗產率=定量。1.65 g (5.0 mmol) of the product prepared in step 16.2 was placed in a 120 mL ethanol/acetic acid mixture (v/v = 1/1) in a hydrogenation autoclave, and 0.150 g of platinum oxide (IV) was added under an inert atmosphere. ). The mixture was stirred at 4 bar hydrogen pressure for 4 hours at room temperature. After filtration through thin glass fiber paper and evaporation to dryness under reduced pressure, the oily residue was dissolved in chloroform and washed with 1N aqueous NaOH. Dried over Na 2 SO 4 organic phase was filtered and concentrated in vacuo. 1.5 g of the expected product was obtained as a brown oil which was used in the next step. Crude yield = quantitative.

16.4：2-氯-8-乙基-7-甲基胺基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺16.4: 2-Chloro-8-ethyl-7-methylamino-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide

將2 g(7.47 mmol)在步驟2.6中製備的產物於40 mL無水NMP中之懸浮液在冰水浴上冷卻，且一次性添加0.45 g(11.21 mmol)60%氫化鈉。在冷卻下攪拌混合物直至氣體析出停止，且隨後在室溫下放置10分鐘。將溶液在冰水浴上冷卻且逐滴添加0.56 mL(8.97 mmol)碘甲烷於5 mL無水NMP中之溶液。使混合物緩慢溫至室溫，並攪拌24小時。添加冰，且接著將反應混合物傾入水中。藉由添加1 N HCl水溶液使所得混合物酸化至pH 1。使所得混合物在室溫下靜置48小時，且添加乙酸乙酯。用力攪拌此混合物1小時。在藉由沈降分離各相之後，經Na2 SO4 乾燥有機相，過濾且在真空下濃縮。在***中濕磨所獲黃色固體，藉由抽吸排乾，以戊烷沖洗並在烘箱中在真空下乾燥。獲得0.7 g呈黃色固體狀之預期產物與起始物質之90/10混合物(LC/MS)，其按原樣用於下一步中。A suspension of 2 g (7.47 mmol) of the product prepared in step 2.6 in 40 mL of dry NMP was cooled on an ice water bath and 0.45 g (11.21 mmol) of 60% sodium hydride was added in one portion. The mixture was stirred under cooling until the gas evolution stopped, and then left at room temperature for 10 minutes. The solution was cooled on an ice water bath and a solution of 0.56 mL (8.97 mmol) of methyl iodide in 5 mL anhydrous NMP was added dropwise. The mixture was slowly warmed to room temperature and stirred for 24 hours. Ice was added and the reaction mixture was then poured into water. The resulting mixture was acidified to pH 1 by the addition of 1 N aqueous HCl. The resulting mixture was allowed to stand at room temperature for 48 hours, and ethyl acetate was added. The mixture was vigorously stirred for 1 hour. After the phases were separated by settling, dried over Na 2 SO 4 the organic phase was dried, filtered and concentrated in vacuo. The yellow solid obtained was triturated in diethyl ether, drained by suction, rinsed with pentane and dried in vacuo in vacuo. 0.7 g of a 90/10 mixture (LC/MS) of the desired product and the starting material as a yellow solid was obtained which was used in the next step.

16.5：8-乙基-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-7-甲基胺基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺16.5: 8-Ethyl-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]phenylamino}-7-methyl Amino-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide

向0.5 g(1.77 mmol)在步驟16.4中製備的產物於5 mL無水DMF中之懸浮液中添加1.07 g(3.55 mmol)在步驟16.3中製備的產物，且在100℃下加熱反應混合物4小時。將其蒸發至乾燥且藉由矽膠管柱層析，以二氯甲烷/甲醇梯度(100/0至95/5)溶離來純化殘餘物。在甲醇中濕磨之後，獲得0.08 g呈白色固體狀之預期產物。To a suspension of 0.5 g (1.77 mmol) of the product obtained in step 16.4 in 5 mL of dry DMF was added 1.07 g (3.55 mmol) of the product which was obtained in step 16.3, and the reaction mixture was heated at 100 ° C for 4 hours. It was evaporated to dryness and the residue was purified eluting with EtOAc EtOAc. After wet milling in methanol, 0.08 g of the desired product was obtained as a white solid.

11 6.6：8-乙基-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-7-甲基胺基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽6.6: 8-Ethyl-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]phenylamino}-7-methyl Amino-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide hydrochloride

向0.08 g(0.15 mmol)在步驟16.5中製備的產物於6 mL二氯甲烷/甲醇混合物(v/v=1/1)中之溶液中添加0.44 mL(0.44 mmol)氫氯醚之1M溶液。在室溫下攪拌混合物1小時，且接著添加***。藉由抽吸排乾固體，以戊烷沖洗並在烘箱中在真空下乾燥。最終獲得0.09 g呈黃色固體狀之預期產物。產率(二鹽酸鹽)=99%。M+H+ =548。To a solution of 0.08 g (0.15 mmol) of the product obtained in step 16.5 in 6 mL dichloromethane / methanol mixture (v / v = 1 / 1) was added 0.44 mL (0.44 mmol) of 1M solution of hydrogen chloride. The mixture was stirred at room temperature for 1 hour, and then diethyl ether was added. The solid was drained by suction, rinsed with pentane and dried under vacuum in an oven. Finally, 0.09 g of the expected product was obtained as a yellow solid. Yield (dihydrochloride) = 99%. M+H + = 548.

1 H NMR(DMSO-d6;400 MHz):δ11.75(寬s,1H);11.1(寬s,1H);10.9(寬s,1H);8.9(s,1H);8.8(s,1H);8.05(寬s,1H);7.9(d,1H);7.0(s,1H);6.85(d,1H);4.3(q,2H);3.85(s,3H);3.65(m,2H),3.35(m,2H);2.9-3.2(m,4H);2.8(m,1H);2.75(s,3H),2.0(m,4H);1.2(t,3H)。 1 H NMR (DMSO-d6; 400 MHz): δ11.75 ( broad s, 1H); 11.1 (broad s, 1H); 10.9 (broad s, 1H); 8.9 (s , 1H); 8.8 (s, 1H ; 8.05 (width s, 1H); 7.9 (d, 1H); 7.0 (s, 1H); 6.85 (d, 1H); 4.3 (q, 2H); 3.85 (s, 3H); 3.65 (m, 2H) ), 3.35 (m, 2H); 2.9-3.2 (m, 4H); 2.8 (m, 1H); 2.75 (s, 3H), 2.0 (m, 4H); 1.2 (t, 3H).

實例17：7-胺基-8-(2-羥基-2-甲基丙基)-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽Example 17: 7-Amino-8-(2-hydroxy-2-methylpropyl)-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)peri Pyridin-4-yl]phenylamino}-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide hydrochloride

17.1：2-氯-4-(2-羥基-2-甲基丙基胺基)嘧啶-5-甲酸17.1: 2-Chloro-4-(2-hydroxy-2-methylpropylamino)pyrimidine-5-carboxylic acid

將19.9 g(86.73 mmol)2,4-二氯-5-嘧啶甲酸於155 mL THF中之懸浮液於冰浴上冷卻至2-5℃，且逐滴添加8.5 g(95.40 mmol)1-胺基-2-甲基-2-丙醇及36.3 mL(260.19 mmol)三乙胺於60 mL THF中之溶液。在室溫下攪拌混合物隔夜。添加乙酸乙酯及水。在藉由沈降分離各相之後，以1N HCl水溶液酸化水相至pH 2。藉由過濾分離沈澱物以得到12.6 g呈淡黃色固體狀之預期產物，其按原樣用於下一步中。產率=59%。A suspension of 19.9 g (86.73 mmol) of 2,4-dichloro-5-pyrimidinecarboxylic acid in 155 mL of THF was cooled to 2-5 ° C on ice bath and 8.5 g (95.40 mmol) of 1-amine was added dropwise. A solution of benzyl-2-methyl-2-propanol and 36.3 mL (260.19 mmol) of triethylamine in 60 mL THF. The mixture was stirred overnight at room temperature. Ethyl acetate and water were added. After separating the phases by sedimentation, the aqueous phase was acidified to pH 2 with 1N aqueous HCl. The precipitate was isolated by filtration to give 12.2 g of the desired product as a pale yellow solid which was used in the next. Yield = 59%.

17.2：2-氯-4-(2-羥基-2-甲基丙基胺基)嘧啶-5-甲酸氟化物17.2: 2-Chloro-4-(2-hydroxy-2-methylpropylamino)pyrimidine-5-carboxylic acid fluoride

向含有12.64 g(51.45 mmol)在步驟17.1中製備的酸及7.89 mL(56.60 mmol)三乙胺於250 mL二氯甲烷中之溶液中添加6.51 mL(77.18 mmol)三聚氟化氰。在室溫下攪拌混合物隔夜且以590 mL CH2 Cl2 及190 mL冰冷的NaHCO3 水溶液稀釋該溶液。以250 mL冰冷的NaHCO3 水溶液洗滌有機相兩次且經MgSO4 乾燥。接著在減壓下蒸發掉溶劑。獲得12.3 g呈黃色油狀之預期產物，其緩慢凝固，且其按原樣用於下一步中。產率=96%。To a solution containing 12.64 g (51.45 mmol) of the acid prepared in step 17.1 and 7.89 mL (56.60 mmol) of triethylamine in 250 mL of dichloromethane was added 6.51 mL (77.18 mmol). The mixture was stirred at room temperature overnight and the solution was diluted with 590 mL CH 2 Cl 2 and 190 mL ice cold NaHCO 3 aqueous. The organic phase was washed twice at NaHCO 3 solution and 250 mL of ice-cold dried over MgSO 4. The solvent was then evaporated under reduced pressure. 12.3 g of the expected product as a yellow oil was obtained which slowly solidified and was used in the next step. Yield = 96%.

17.3：7-胺基-2-氯-8-(2-羥基-2-甲基丙基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺17.3: 7-Amino-2-chloro-8-(2-hydroxy-2-methylpropyl)-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6- Formamide

向已於冰浴上冷卻至2-5℃的4.4 g(52.36 mmol)氰基乙醯胺於70 mL無水DMF中的溶液中逐份添加4.19 g(104.72 mmol)60%氫化鈉。在2-5℃下攪拌混合物15分鐘，且接著將此懸浮液快速添加至已預冷卻至2-5℃的12.35 g(49.87 mmol)在步驟17.2中製備的酸氟化物於70 mL無水DMF中之溶液中。在室溫下攪拌混合物隔夜且接著於冰浴上冷卻至2-5℃，且逐份添加2.09 g(52.36 mmol)60%氫化鈉。在室溫下攪拌反應混合物3小時且隨後傾入冰、100 mL水與150 mL 1 N HCl水溶液之混合物中。藉由過濾分離所形成之黃色沈澱物，以水沖洗且接著在烘箱中乾燥。在甲醇中濕磨且於烘箱中乾燥之後，最終獲得8.84 g呈黃色固體狀之預期產物。產率=57%。4.14 g (104.72 mmol) of 60% sodium hydride was added portionwise to a solution of 4.4 g (52.36 mmol) of cyanoacetamide in 70 mL of dry DMF which had been cooled to 2-5 ° C on ice. The mixture was stirred at 2-5 °C for 15 minutes, and then the suspension was quickly added to 12.35 g (49.87 mmol) of the acid fluoride prepared in step 17.2 in 70 mL of anhydrous DMF that had been precooled to 2-5 °C. In the solution. The mixture was stirred at room temperature overnight and then cooled to 2-5 &lt;0&gt;C on an ice bath and 2.09 g (52.36 mmol) of 60% sodium hydride. The reaction mixture was stirred at room temperature for 3 hours and then poured into a mixture of ice, 100 mL water and 150 mL 1 N aqueous HCl. The yellow precipitate formed by filtration was separated, rinsed with water and then dried in an oven. After wet milling in methanol and drying in an oven, 8.84 g of the desired product was obtained as a yellow solid. Yield = 57%.

17.4：7-胺基-8-(2-羥基-2-甲基丙基)-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺17.4:7-Amino-8-(2-hydroxy-2-methylpropyl)-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperidine 4-yl]phenylamino}-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide

向0.82 g(2.62 mmol)在步驟17.3中製備的產物於6.4 mL無水NMP中之懸浮液中添加1.59 g(5.25 mmol)在步驟16.3中製備的產物，且在110℃下加熱反應混合物1.5小時。將其蒸發至乾燥且藉由矽膠管柱層析，以含有痕量濃NH4 OH水溶液之二氯甲烷/甲醇梯度(100/0至95/5)溶離來純化殘餘物。獲得0.70 g呈白色固體狀之預期產物。產率=46%。To a suspension of 0.82 g (2.62 mmol) of the product obtained in step 17.3 in 6.4 mL of dry NMP was added 1.59 g (5.25 mmol) of the product obtained in step 16.3, and the reaction mixture was heated at 110 ° C for 1.5 hours. Evaporated to dryness and by chromatography on silica gel column, methylene chloride containing traces of concentrated NH 4 OH of an aqueous solution / methanol gradient (100/0 to 95/5) The residue was purified fractions. 0.70 g of the expected product was obtained as a white solid. Yield = 46%.

17.5：7-胺基-8-(2-羥基-2-甲基丙基)-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽17.5: 7-Amino-8-(2-hydroxy-2-methylpropyl)-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperidine 4-yl]phenylamino}-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide hydrochloride

將0.70 g(1.22 mmol)在步驟17.4中製備的產物於17 mL甲醇中之溶液於冰浴上冷卻，且添加0.91 mL(3.65 mmol)氯化氫於二噁烷中之4 N溶液。在室溫下攪拌混合物30分鐘且隨後傾入***中。藉由抽吸排乾固體，以戊烷沖洗並在烘箱中在真空下乾燥。最終獲得0.64 g呈白色固體狀之預期產物。產率(二鹽酸鹽)=91%。m.p.>260℃。M+H+= 5781 H NMR(DMSO-d6 +D2 O;400 MHz): 8.9(s,1H);7.6(d,1H);6.95(s,1H);6.85(d,1H);4.8(極寬s,2H);3.8(s,3H);3.6(m,2H),3.4(m,2H);3.1(m,2H);2.8-2.95(m,3H);2.05(m,2H);1.95(m,2H);1.1(極寬s,6H)。A solution of 0.70 g (1.22 mmol) of the product obtained in step 17.4 in 17 mL of MeOH was cooled on ice bath and a solution of &lt;RTI ID=0.0&gt;&gt; The mixture was stirred at room temperature for 30 minutes and then poured into diethyl ether. The solid was drained by suction, rinsed with pentane and dried under vacuum in an oven. Finally, 0.64 g of the expected product was obtained as a white solid. Yield (dihydrochloride) = 91%. Mp>260 °C. M+H += 578 1 H NMR (DMSO-d 6 + D 2 O; 400 MHz): 8.9 (s, 1H); 7.6 (d, 1H); 6.95 (s, 1H); 6.85 (d, 1H) ; 4.8 (extremely wide s, 2H); 3.8 (s, 3H); 3.6 (m, 2H), 3.4 (m, 2H); 3.1 (m, 2H); 2.8-2.95 (m, 3H); 2.05 (m , 2H); 1.95 (m, 2H); 1.1 (extremely wide s, 6H).

實例18：7-胺基-2-[4-(4-乙基哌嗪-1-基)-2-甲氧基苯基胺基]-8-(2-羥基-2-甲基丙基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽Example 18: 7-Amino-2-[4-(4-ethylpiperazin-1-yl)-2-methoxyphenylamino]-8-(2-hydroxy-2-methylpropyl) )-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide hydrochloride

18.1：1-乙基-4-(3-甲氧基-4-硝基苯基)哌嗪18.1:1-Ethyl-4-(3-methoxy-4-nitrophenyl)piperazine

將3.42 g(20 mmol)4-氟-2-甲氧基-1-硝基苯、2.67 mL(21 mmol)1-乙基哌嗪與5.14 mL(30 mmol)二異丙基乙胺於25 mL乙腈中之混合物在85℃下加熱2.5小時且接著在95℃下加熱1小時，且隨後攪拌隔夜同時使其恢復至室溫。蒸發掉乙腈且接著將殘餘物溶解於50 mL***及25 mL水中。以***萃取水相。合併有機相，經Na2 SO4 乾燥，過濾且在真空下濃縮。在***/環己烷混合物(1/1)中濕磨所獲油狀物且藉由過濾分離沈澱物，以戊烷沖洗並在烘箱中乾燥。最終獲得4.1 g預期產物。產率=77%。3.42 g (20 mmol) 4-fluoro-2-methoxy-1-nitrobenzene, 2.67 mL (21 mmol) 1-ethylpiperazine and 5.14 mL (30 mmol) diisopropylethylamine in 25 The mixture in mL acetonitrile was heated at 85 °C for 2.5 hours and then at 95 °C for 1 hour, and then stirred overnight until it was allowed to return to room temperature. The acetonitrile was evaporated and the residue was dissolved in 50 mL diethyl ether and 25 mL water. The aqueous phase was extracted with diethyl ether. The combined organic phases were dried over Na 2 SO 4, filtered and concentrated in vacuo. The oil obtained was wet-milled in a mixture of diethyl ether/cyclohexane (1/1) and the precipitate was separated by filtration, rinsed with pentane and dried in oven. Finally, 4.1 g of the expected product was obtained. Yield = 77%.

18.2：4-(4-乙基哌嗪-1-基)-2-甲氧基苯胺18.2: 4-(4-Ethylpiperazin-1-yl)-2-methoxyaniline

將於25 mL乙酸乙酯/乙醇混合物(v/v=1/1)中的4.05 g(15.27 mmol)在步驟18.1中製備的產物置於氫化高壓釜中，且在惰性氛圍下添加0.32 g 10%鈀/木炭。在室溫下，在2.5巴氫氣壓力下攪拌混合物2小時。在經由薄玻璃纖維紙過濾且在減壓下蒸發之後，獲得3.51 g呈紫色固體狀之預期產物，其按原樣用於下一步中。產率=98%。4.05 g (15.27 mmol) of the product prepared in step 18.1 in 25 mL of ethyl acetate/ethanol mixture (v/v = 1/1) was placed in a hydrogenation autoclave and 0.32 g of 10 was added under an inert atmosphere. % palladium / charcoal. The mixture was stirred at 2.5 bar hydrogen pressure for 2 hours at room temperature. After filtration through thin glass fiber paper and evaporation under reduced pressure, 3.51 g of the desired product was obtained as a purple solid, which was used in the next step. Yield = 98%.

18.3：7-胺基-2-[4-(4-乙基哌嗪-1-基)-2-甲氧基苯基胺基]-8-(2-羥基-2-甲基丙基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺18.3: 7-Amino-2-[4-(4-ethylpiperazin-1-yl)-2-methoxyphenylamino]-8-(2-hydroxy-2-methylpropyl) -5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide

向1.0 g(3.21 mmol)在步驟17.3中製備的產物於5 mL無水NMP中之懸浮液中添加1.51 g(6.42 mmol)在步驟18.2中製備的產物，且在100℃下加熱反應混合物2小時。使其冷卻至室溫且接著以NaHCO3 水溶液稀釋。攪拌混合物隔夜且藉由過濾分離沈澱物並接著在烘箱中乾燥。藉由矽膠管柱層析，以含有痕量濃NH4 OH水溶液之二氯甲烷/甲醇梯度(100/0至95/5)溶離來純化殘餘物。最後在甲醇中濕磨且在烘箱中乾燥之後，獲得0.46 g預期產物。產率=28%。To a suspension of 1.0 g (3.21 mmol) of the product obtained in step 17.3 in 5 mL of dry NMP was added 1.51 g (6.42 mmol) of the product which was obtained in step 18.2, and the reaction mixture was heated at 100 ° C for 2 hours. Then allowed to cool to room temperature and diluted with aqueous NaHCO 3. The mixture was stirred overnight and the precipitate was separated by filtration and then dried in an oven. By silica gel column chromatography, methylene chloride containing a trace of concentrated NH 4 OH of an aqueous solution / methanol gradient (100/0 to 95/5) The residue was purified fractions. After finally wet milling in methanol and drying in an oven, 0.46 g of the desired product was obtained. Yield = 28%.

18.4：7-胺基-2-[4-(4-乙基哌嗪-1-基)-2-甲氧基苯基胺基]-8-(2-羥基-2-甲基丙基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽18.4:7-Amino-2-[4-(4-ethylpiperazin-1-yl)-2-methoxyphenylamino]-8-(2-hydroxy-2-methylpropyl) -5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide hydrochloride

將0.46 g(0.9 mmol)在步驟18.3中製備的產物於13 mL甲醇中之溶液於冰浴上冷卻，且添加0.67 mL(2.69 mmol)氯化氫於二噁烷中之4 N溶液。在室溫下攪拌混合物30分鐘且接著傾入***中。藉由抽吸排乾固體，以戊烷沖洗並在烘箱中在真空下乾燥。最終獲得0.47 g呈黃色固體狀之預期產物。產率(二鹽酸鹽)=90%。m.p.=222℃(分解)。M+H+ =511。A solution of 0.46 g (0.9 mmol) of the product obtained in step 18.3 in 13 mL of MeOH was cooled on ice bath and &lt;RTIgt;&lt;/RTI&gt; The mixture was stirred at room temperature for 30 minutes and then poured into diethyl ether. The solid was drained by suction, rinsed with pentane and dried under vacuum in an oven. Finally, 0.47 g of the expected product was obtained as a yellow solid. Yield (dihydrochloride) = 90%. Mp = 222 ° C (decomposition). M+H + = 511.

1 H NMR(DMSO-d6 ,400 MHz):δ11.5(大s,1H);10.9(大s,1H);9.1(大s,1H);8.9(大s,1H);8.4(大s,1H);7.45(d,1H);6.75(d,1H);6.6(dd,1H);4.8(大s trs,1H);3.70-4.20(s+m,9H);3.0-3.3(m,6H);1.3(t,3H);1.05(大s trs,6H)。 1 H NMR (DMSO-d 6 , 400 MHz): δ 11.5 (large s, 1H); 10.9 (large s, 1H); 9.1 (large s, 1H); 8.9 (large s, 1H); 8.4 (large s, 1H); 7.45 (d, 1H); 6.75 (d, 1H); 6.6 (dd, 1H); 4.8 (large s tr s, 1H); 3.70-4.20 (s+m, 9H); 3.0-3.3 (m, 6H); 1.3 (t, 3H); 1.05 (large s tr s, 6H).

實例19：7-胺基-2-[4-(4-乙基哌啶-1-基)-2-甲氧基苯基胺基]-8-(2-羥基-2-甲基丙基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽Example 19: 7-Amino-2-[4-(4-ethylpiperidin-1-yl)-2-methoxyphenylamino]-8-(2-hydroxy-2-methylpropyl) )-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide hydrochloride

19.1：4-[4-(7-胺基-6-胺甲醯基-8-(2-羥基-2-甲基丙基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-2-基胺基)-3-甲氧基苯基]哌啶-1-甲酸第三丁酯19.1: 4-[4-(7-Amino-6-aminecarbamido-8-(2-hydroxy-2-methylpropyl)-5-one-5,8-dihydropyrido[2] ,3-d]pyrimidin-2-ylamino)-3-methoxyphenyl]piperidine-1-carboxylic acid tert-butyl ester

將2.0 g(6.42 mmol)在步驟17.3中製備的產物與2.95 g(9.62 mmol)在步驟4.3中製備的產物於18 mL NMP中之混合物置於圓底燒瓶中。在110℃下加熱懸浮液2小時。添加30 mL水及接著添加5 mL NaHCO3 飽和水溶液且藉由抽吸排乾所形成之沈澱物並接著在烘箱中乾燥。在甲醇中濕磨粗固體且接著在烘箱中乾燥。獲得2.38 g呈粉色固體狀之預期產物，其按原樣用於下一步中。產率=64%。A mixture of 2.0 g (6.42 mmol) of the product prepared in step 17.3 and 2.95 g (9.62 mmol) of the product obtained in step 4.3 in 18 mL of NMP was placed in a round bottom flask. The suspension was heated at 110 ° C for 2 hours. 30 mL of water was added followed by 5 mL of a saturated aqueous solution of NaHCO 3 and the precipitate formed by suction was drained and then dried in an oven. The crude solid was wet milled in methanol and then dried in an oven. 2.38 g of the expected product was obtained as a pink solid which was used in the next step. Yield = 64%.

19.2：7-胺基-8-(2-羥基-2-甲基丙基)-2-(2-甲氧基-4-哌啶-4-基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽19.2: 7-Amino-8-(2-hydroxy-2-methylpropyl)-2-(2-methoxy-4-piperidin-4-ylphenylamino)-5-oneyl- 5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide hydrochloride

將2.28 g(3.92 mmol)在步驟19.1中製備的產物於70 mL二氯甲烷中之懸浮液於冰水浴上冷卻，且緩慢添加9.8 mL(39.20 mmol)氯化氫於二噁烷中之4 N溶液。在室溫下攪拌混合物1小時且添加***。藉由抽吸排乾固體，以戊烷沖洗並在烘箱中乾燥。獲得2.2 g呈米色固體狀之預期產物，其按原樣用於下一步中。產率(二鹽酸鹽)=定量。A suspension of 2.28 g (3.92 mmol) of the product obtained in step 19.1 in 70 mL of dichloromethane was cooled on ice water bath, and 9.8 mL (39.20 mmol) of hydrogen chloride in 4N solution in dioxane was slowly added. The mixture was stirred at room temperature for 1 hour and diethyl ether was added. The solid was drained by suction, rinsed with pentane and dried in an oven. 2.2 g of the expected product as a beige solid was obtained which was used in the next step. Yield (dihydrochloride) = quantitative.

19.3：7-胺基-8-(2-羥基-2-甲基丙基)-2-[4-(4-乙基哌啶-1-基)-2-甲氧基苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺19.3: 7-Amino-8-(2-hydroxy-2-methylpropyl)-2-[4-(4-ethylpiperidin-1-yl)-2-methoxyphenylamino] -5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide

將0.6 g(1.08 mmol)在步驟19.2中製備的鹽酸鹽懸浮於14 mL 1,2-二氯乙烷中，且添加0.56 mL(3.25 mmol)二異丙基乙胺、0.30 mL(5.41 mmol)乙醛並接著逐份添加0.46 g(2.16 mmol)三乙醯氧基硼氫化鈉。攪拌混合物2小時且傾入0.25 N氫氧化鈉溶液中，並添加二氯甲烷。在藉由沈降分離各相之後，以二氯甲烷萃取水相且合併有機相，經Na2 SO4 乾燥，過濾並在真空下濃縮。回收0.58 g淡棕色固體，且藉由矽膠管柱層析，以二氯甲烷/甲醇梯度(95/5至90/10)溶離來純化其。獲得0.26 g呈黃色固體狀之預期產物。產率=47%。0.6 g (1.08 mmol) of the hydrochloride salt prepared in step 19.2 was suspended in 14 mL of 1,2-dichloroethane, and 0.56 mL (3.25 mmol) diisopropylethylamine, 0.30 mL (5.41 mmol) Acetaldehyde and then 0.46 g (2.16 mmol) of sodium triethoxysulfonate hydride were added portionwise. The mixture was stirred for 2 hours and poured into a 0.25 N sodium hydroxide solution, and dichloromethane was added. After the phases were separated by settling, the aqueous phase was extracted with dichloromethane and the combined organic phases were dried over Na 2 SO 4, filtered and concentrated in vacuo. 0.58 g of a light brown solid was recovered and purified by chromatography on a silica gel column eluting with dichloromethane/methanol gradient (95/5 to 90/10). Obtained 0.26 g of the expected product as a yellow solid. Yield = 47%.

19.4：7-胺基-8-(2-羥基-2-甲基丙基)-2-[4-(4-乙基哌啶-1-基)-2-甲氧基苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽19.4:7-Amino-8-(2-hydroxy-2-methylpropyl)-2-[4-(4-ethylpiperidin-1-yl)-2-methoxyphenylamino] -5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide hydrochloride

向0.25 g(0.50 mmol)在步驟19.3中製備的產物於10 mL二氯甲烷/甲醇混合物(4/1)中之溶液中添加2 mL(2 mmol)1.0 M氫氯醚。在室溫下攪拌混合物10分鐘且接著以***稀釋。藉由抽吸排乾沈澱物，以***及戊烷沖洗並在真空下乾燥。獲得0.28 g呈黃色固體狀之預期產物。產率(二鹽酸鹽)=96%。m.p.=200℃(分解)。M+H+ =510。To a solution of 0.25 g (0.50 mmol) of the product obtained in step 19.3 in 10 mL dichloromethane / methanol mixture (4 / 1) was added 2 mL (2 mmol) of 1.0 M hydrochloroether. The mixture was stirred at room temperature for 10 minutes and then diluted with diethyl ether. The precipitate was drained by suction, rinsed with diethyl ether and pentane and dried under vacuum. Obtained 0.28 g of the expected product as a yellow solid. Yield (dihydrochloride) = 96%. Mp = 200 ° C (decomposition). M+H + = 510.

1 H NMR(DMSO-d6 ,400 MHz):δ11.5(大s,1H);10.4(大s,1H);9.1(s,1H);8.95(s,1H);8.45(大s,1H);7.6(d,1H);7.0(s,1H);6.85(d,1H);4.8(大s,2H);3.85(s,3H);3.6(m,2H);3.1(m,2H);3.05(m,2H);2.85(m,1H);2.1-2.2(m,4H);1.3(t,3H);1.1(大s trs,6H) 1 H NMR (DMSO-d 6 , 400 MHz): δ 11.5 (large s, 1H); 10.4 (large s, 1H); 9.1 (s, 1H); 8.95 (s, 1H); 8.45 (large s, 1H); 7.6 (d, 1H); 7.0 (s, 1H); 6.85 (d, 1H); 4.8 (large s, 2H); 3.85 (s, 3H); 3.6 (m, 2H); 3.1 (m, 2H); 3.05 (m, 2H); 2.85 (m, 1H); 2.1-2.2 (m, 4H); 1.3 (t, 3H); 1.1 (large s tr s,6H)

實例20：7-胺基-2-(2-甲氧基-4-哌啶-4-基苯基胺基)-5-酮基-8-苯基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽Example 20: 7-Amino-2-(2-methoxy-4-piperidin-4-ylphenylamino)-5-keto-8-phenyl-5,8-dihydropyridin[ 2,3-d]pyrimidine-6-methanamine hydrochloride

20.1：2-甲基硫基-4-苯基胺基-5-嘧啶甲酸乙酯20.1: Ethyl 2-methylthio-4-phenylamino-5-pyrimidinecarboxylate

向5.0 g(21.49 mmol)4-氯-2-甲基硫基-5-嘧啶甲酸乙酯及4.9 mL(53.72 mmol)苯胺於75 mL THF中之溶液中添加7.49 mL(53.72 mmol)三乙胺。在室溫下攪拌混合物隔夜。在蒸發掉THF之後，添加1 N HCl水溶液且以乙酸乙酯萃取混合物。以NaHCO3 飽和水溶液及接著以NaCl溶液洗滌有機相。經MgSO4 乾燥有機相。在過濾之後，濃縮濾液以得到3.99 g呈米色固體狀之預期產物，其按原樣用於下一步中。產率=64%。Add 7.49 mL (53.72 mmol) of triethylamine to a solution of 5.0 g (21.49 mmol) of 4-chloro-2-methylthio-5-pyrimidinecarboxylate and 4.9 mL (53.72 mmol) aniline in 75 mL THF. . The mixture was stirred overnight at room temperature. After evaporating the THF, 1 N aqueous HCl solution was added and the mixture was extracted with ethyl acetate. In saturated NaHCO 3 solution and then the organic phase was washed with NaCl solution. The organic phase was dried over MgSO 4. After filtration, the filtrate was concentrated to give 3.99 g of the desired product as a white solid. Yield = 64%.

20.2：2-甲基硫基-4-苯基胺基-5-嘧啶甲酸20.2: 2-Methylthio-4-phenylamino-5-pyrimidinecarboxylic acid

將含有3.98 g(13.75 mmol)在步驟20.1中製備的產物、34.4 mL(34.4 mmol)1 N NaOH及35 mL乙醇之混合物在室溫下攪拌隔夜。在減壓下蒸發掉乙醇且將殘餘物於100 mL水中稀釋。添加65 mL 1 N HCl水溶液且藉由抽吸排乾所形成之沈澱物。以水沖洗固體且在真空下乾燥。獲得2.88 g呈米色固體狀之預期產物。產率=92%。A mixture containing 3.98 g (13.75 mmol) of the product prepared in step 20.1, 34.4 mL (34.4 mmol) 1 N NaOH and 35 mL of ethanol was stirred overnight at room temperature. Ethanol was evaporated under reduced pressure and the residue was diluted in 100 mL water. 65 mL of 1 N aqueous HCl solution was added and the precipitate formed was drained by suction. The solid was rinsed with water and dried under vacuum. 2.88 g of the expected product was obtained as a beige solid. Yield = 92%.

20.3：2-甲基硫基-4-苯基胺基-5-嘧啶甲酸氟化物20.3: 2-methylthio-4-phenylamino-5-pyrimidinecarboxylic acid fluoride

向含有2.88 g(11.02 mmol)在步驟20.2中製備的產物及2.1 mL(15.0 mmol)三乙胺於55 mL CH2 Cl2 中之溶液中添加1.40 mL(16.53 mmol)三聚氟化氰。在室溫下攪拌混合物隔夜且以50 mL冰冷的NaHCO3 水溶液洗滌兩次。以75 mL冰冷水洗滌有機相且經MgSO4 乾燥。隨後在減壓下蒸發掉溶劑。獲得3.0 g呈黃色固體狀之預期產物。產率為定量的。To a solution containing 2.88 g (11.02 mmol) of the product obtained in step 20.2 and 2.1 mL (15.0 mmol) of triethylamine in 55 mL CH 2 Cl 2 was added 1.40 mL (16.53 mmol). The mixture was stirred overnight at room temperature and with NaHCO 3 solution washed twice with 50 mL of ice-cold. Drying to 75 mL of ice-cold water and the organic phase was washed over MgSO 4. The solvent was then evaporated under reduced pressure. 3.0 g of the expected product are obtained as a yellow solid. The yield is quantitative.

22 0.4：7-胺基-2-甲基硫基-5-酮基-8-苯基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺0.4:7-Amino-2-methylthio-5-keto-8-phenyl-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide

向已冷卻至0-5℃的1.0 g(11.96 mmol)氰基乙醯胺於17 mL無水DMF中之溶液中添加0.96 g(23.93 mmol)60%NaH。添加之後，在室溫下攪拌混合物10分鐘且接著在冰水浴上再次冷卻，且添加3.0 g在步驟20.3中製備的酸氟化物(11.39 mmol)於17 mL無水DMF中之溶液。在室溫下攪拌反應混合物隔夜。於冰水浴上冷卻反應混合物且添加0.48 g(11.96 mmol)60% NaH。在室溫下攪拌反應混合物5小時且隨後傾入0.5 N冰冷之HCl水溶液中。藉由過濾分離所形成之沈澱物，以水沖洗，藉由抽吸排乾並接著在烘箱中乾燥。獲得3.44 g主要由呈非環化形式之預期產物構成的黃色固體。To a solution of 1.0 g (11.96 mmol) of cyanoacetamide in 17 mL of dry DMF cooled to 0-5 ° C was added 0.96 g (23.93 mmol) of 60% NaH. After the addition, the mixture was stirred at room temperature for 10 minutes and then cooled again on an ice water bath, and 3.0 g of a solution of the acid fluoride (11.39 mmol) prepared in step 20.3 in 17 mL of anhydrous DMF was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was cooled on an ice water bath and 0.48 g (11.96 mmol) of 60% NaH. The reaction mixture was stirred at room temperature for 5 hours and then poured into 0.5 N ice cold EtOAc. The precipitate formed by filtration was separated, rinsed with water, drained by suction and then dried in an oven. 3.44 g of a yellow solid consisting essentially of the expected product in an acyclic form is obtained.

將上述所獲固體溶解於50 mL正丁醇中且回流溶液隔夜。在冷卻至室溫之後，藉由過濾分離沈澱物並在烘箱中乾燥。獲得1.69 g呈黃色固體狀之預期產物。產率=45%。The solid obtained above was dissolved in 50 mL of n-butanol and the solution was refluxed overnight. After cooling to room temperature, the precipitate was separated by filtration and dried in an oven. 1.69 g of the expected product was obtained as a yellow solid. Yield = 45%.

20.5：7-胺基-2-甲烷磺醯基-5-酮基-8-苯基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺及7-胺基-2-甲烷亞磺醯基-5-酮基-8-苯基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺20.5: 7-Amino-2-methanesulfonyl-5-keto-8-phenyl-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide and 7-amine Methyl-2-methanesulfinyl-5-keto-8-phenyl-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide

向1.69 g(5.16 mmol)在步驟20.4中獲得的化合物於100 mL氯仿中之懸浮液中添加3.18 g(12.91 mmol)間氯過苯甲酸。在室溫下攪拌混合物24小時，且添加0.44 g(2.58 mmol)間氯過苯甲酸。攪拌此混合物24小時且接著藉由過濾分離出不溶性物質。在真空下濃縮濾液且接著在甲醇中濕磨並在烘箱中乾燥。獲得1.12 g由預期碸與亞碸之混合物(藉由1 H NMR得知為約80/20)構成的淡黃色固體。To a suspension of 1.69 g (5.16 mmol) of the compound obtained in step 20.4 in 100 mL of chloroform was added 3.18 g (12.91 mmol) of m-chloroperbenzoic acid. The mixture was stirred at room temperature for 24 hours, and 0.44 g (2.58 mmol) of m-chloroperbenzoic acid was added. The mixture was stirred for 24 hours and then the insoluble material was separated by filtration. The filtrate was concentrated under vacuum and then wet-milled in methanol and dried in an oven. 1.12 g of a pale yellow solid consisting of the expected mixture of hydrazine and hydrazine (about 80/20 by 1 H NMR) was obtained.

20.6 4-[4-(7-胺基-6-胺甲醯基-5-酮基-8-苯基-5,8-二氫吡啶并[2,3-d]嘧啶-2-基胺基)-3-甲氧基苯基]哌啶-1-甲酸第三丁酯20.6 4-[4-(7-Amino-6-aminocarbamimid-5-one-8-phenyl-5,8-dihydropyrido[2,3-d]pyrimidin-2-ylamine Tert-butyl 3-methylphenyl]piperidine-1-carboxylate

將0.4 g(1.11 mmol)在步驟20.5中所獲的碸與亞碸之混合物及0.51 g(1.67 mmol)在步驟16.3中製備的產物在110℃下於5 mL NMP中加熱6小時。添加水且藉由過濾分離固體並接著在烘箱中乾燥。藉由矽膠管柱層析，以二氯甲烷/甲醇梯度(100/0至97/3)溶離來純化0.42 g固體殘餘物。獲得0.16 g呈淡棕色固體狀之預期產物。產率=46%。0.4 g (1.11 mmol) of the mixture of hydrazine and hydrazine obtained in step 20.5 and 0.51 g (1.67 mmol) of the product prepared in step 16.3 were heated in 10 mL of NMP at 110 ° C for 6 hours. Water was added and the solid was separated by filtration and then dried in an oven. 0.42 g of the solid residue was purified by hydrazine gel column chromatography eluting with dichloromethane/methanol gradient (100/0 to 97/3). 0.16 g of the expected product was obtained as a pale brown solid. Yield = 46%.

20.7：7-胺基-2-(2-甲氧基-4-哌啶-4-基苯基胺基)-5-酮基-8-苯基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽20.7: 7-Amino-2-(2-methoxy-4-piperidin-4-ylphenylamino)-5-keto-8-phenyl-5,8-dihydropyrido[2 ,3-d]pyrimidine-6-formamide hydrochloride

將0.15 g(0.26 mmol)在步驟20.6中製備的產物於4 mLCH2 Cl2 中之溶液於冰浴上冷卻，且添加0.99 mL(3.94 mmol)氯化氫於二噁烷中之4 N溶液。在室溫下攪拌混合物30分鐘且接著傾入***中。藉由抽吸排乾固體，以戊烷沖洗並在烘箱中在真空下乾燥。獲得0.136 g淡粉色固體，且逆相純化以最終得到0.1 g呈黃色固體狀之預期產物。產率(二鹽酸鹽)=68%。m.p.=228℃(分解)。M+H+ =487。The 0.15 g (0.26 mmol) of the product prepared in step 20.6 cooled on 4 mLCH 2 Cl 2 solution in the ice bath, and was added 0.99 mL (3.94 mmol) of hydrogen chloride in dioxane solution of 4 N. The mixture was stirred at room temperature for 30 minutes and then poured into diethyl ether. The solid was drained by suction, rinsed with pentane and dried under vacuum in an oven. 0.136 g of a pale pink solid were obtained, which was purified by reverse phase to give 0.1 g of the desired product as a yellow solid. Yield (dihydrochloride) = 68%. Mp = 228 ° C (decomposition). M+H + = 487.

1 H NMR(DMSO-d6 ,400 MHz):δ11.3(大s,1H);10.25(大s,1H);8.9-9.0(s+m,2H);8.8(m,1H);8.3(s,1H);7.7(m,3H);7.5(m,2H);7.25(大s,1H);7.15(m,1H);6.8(s,1H);6.7(大s,1H);6.3(m,1H);3.95(s,3H);3.4(m,2H);3.0(m,2H);2.75(m,1H);1.75-1.95(m,4H)。 1 H NMR (DMSO-d 6 , 400 MHz): δ 11.3 (large s, 1H); 10.25 (large s, 1H); 8.9-9.0 (s+m, 2H); 8.8 (m, 1H); (s, 1H); 7.7 (m, 3H); 7.5 (m, 2H); 7.25 (large s, 1H); 7.15 (m, 1H); 6.8 (s, 1H); 6.7 (large s, 1H); 6.3 (m, 1H); 3.95 (s, 3H); 3.4 (m, 2H); 3.0 (m, 2H); 2.75 (m, 1H); 1.75-1.95 (m, 4H).

實例21：7-胺基-2-[4-(1-環丙基哌啶-4-基)-2-甲氧基苯基胺基]-8-(2-羥基-2-甲基丙基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽Example 21: 7-Amino-2-[4-(1-cyclopropylpiperidin-4-yl)-2-methoxyphenylamino]-8-(2-hydroxy-2-methylpropane 5-(-5-keto)-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide hydrochloride

21.1：7-胺基-2-[4-(1-環丙基哌啶-4-基)-2-甲氧基苯基胺基]-8-(2-羥基-2-甲基丙基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺21.1: 7-Amino-2-[4-(1-cyclopropylpiperidin-4-yl)-2-methoxyphenylamino]-8-(2-hydroxy-2-methylpropyl) )-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide

向0.46 g(0.83 mmol)在步驟20.7中製備的鹽酸鹽於14 mL無水甲醇中之溶液中連續添加0.42 mL(2.48 mmol)二異丙基乙胺、0.47 mL(8.26 mmol)乙酸、已在60℃下在真空烘箱中預乾燥隔夜之細粉狀3分子篩、0.75 mL(3.72 mmol)(1-乙氧基環丙氧基)三甲基矽烷及0.16 g(2.48 mmol)氰基硼氫化鈉。在80℃下加熱混合物隔夜且蒸發至乾燥。藉由矽膠管柱層析，以二氯甲烷/甲醇梯度(96/4至90/10)溶離來純化所獲殘餘物。最終獲得0.16 g呈白色固體狀之預期產物。產率=37%。To a solution of 0.46 g (0.83 mmol) of the hydrochloride salt prepared in step 20.7 in 14 mL of anhydrous methanol, 0.42 mL (2.48 mmol) of diisopropylethylamine and 0.47 mL (8.26 mmol) of acetic acid were added continuously. Pre-drying overnight fine powder in a vacuum oven at 60 ° C 3 Molecular sieves, 0.75 mL (3.72 mmol) of (1-ethoxycyclopropoxy)trimethylnonane and 0.16 g (2.48 mmol) of sodium cyanoborohydride. The mixture was heated at 80 ° C overnight and evaporated to dryness. The residue obtained was purified by hydrazine gel column chromatography eluting with dichloromethane/methanol gradient (96/4 to 90/10). Finally, 0.16 g of the expected product was obtained as a white solid. Yield = 37%.

21.2：7-胺基-2-[4-(1-環丙基哌啶-4-基)-2-甲氧基苯基胺基]-8-(2-羥基-2-甲基丙基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽21.2: 7-Amino-2-[4-(1-cyclopropylpiperidin-4-yl)-2-methoxyphenylamino]-8-(2-hydroxy-2-methylpropyl )-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide hydrochloride

向0.137 g(0,26 mmol)在步驟21.1中製備的產物於5 mL甲醇中之懸浮液中添加1.05 mL(X mmol)1.0 M氫氯醚。在室溫下攪拌混合物5分鐘且接著以***稀釋。藉由抽吸排乾沈澱物，以***及戊烷沖洗並在真空下乾燥。獲得0.12 g呈黃色固體狀之預期產物。產率(二鹽酸鹽)=77%。To a suspension of 0.137 g (0,26 mmol) of the product obtained in step 21.1 in 5 mL of methanol was added 1.05 mL (X. The mixture was stirred at room temperature for 5 minutes and then diluted with diethyl ether. The precipitate was drained by suction, rinsed with diethyl ether and pentane and dried under vacuum. 0.12 g of the expected product was obtained as a yellow solid. Yield (dihydrochloride) = 77%.

m.p.=206℃(分解)。M+H+ =568Mp = 206 ° C (decomposition). M+H + =568

1 H NMR(DMSO-d6 ,400 MHz):δ11.5(大s,1H);10.7(大s,<1H);10.6(m,1H);9.1(s,1H);8.9(s,1H);8.4(大s,1H);7.6(d,1H);7.0(s,1H);6.85(d,1H);4.8(大s,2H);3.8(s,3H);3.6(m,2H);3.2-3.4(m,3H);3.05(m,1H);2.8(m,2H);2.15(m,2H);.1.95(m,2H);1.15(m,2H);1.0(大s trs,6H);0.8(m,2H)。 1 H NMR (DMSO-d 6 , 400 MHz): δ 11.5 (large s, 1H); 10.7 (large s, <1H); 10.6 (m, 1H); 9.1 (s, 1H); 8.9 (s, 1H); 8.4 (large s, 1H); 7.6 (d, 1H); 7.0 (s, 1H); 6.85 (d, 1H); 4.8 (large s, 2H); 3.8 (s, 3H); 3.6 (m) , 2H); 3.2-3.4 (m, 3H); 3.05 (m, 1H); 2.8 (m, 2H); 2.15 (m, 2H); 1.95 (m, 2H); 1.15 (m, 2H); (large s tr s, 6H); 0.8 (m, 2H).

實例22：7-胺基-8-(2-羥基-2-甲基丙基)-2-{2-甲氧基-4-[1-(2-甲氧基乙基)哌啶-4-基]苯基胺基}-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽Example 22: 7-Amino-8-(2-hydroxy-2-methylpropyl)-2-{2-methoxy-4-[1-(2-methoxyethyl)piperidine-4 -yl]phenylamino}-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide hydrochloride

22.1：7-胺基-2-{4-[1-(2-氯乙基)哌啶-4-基]-2-甲氧基苯基胺基}-8-(2-羥基-2-甲基丙基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺22.1:7-Amino-2-{4-[1-(2-chloroethyl)piperidin-4-yl]-2-methoxyphenylamino}-8-(2-hydroxy-2- Methylpropyl)-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide

向0.60 g(1.08 mmol)在步驟20.7中製備的鹽酸鹽於15 mL無水二氯乙烷中之懸浮液中連續添加0.56 mL(3.25 mmol)二異丙基乙胺、0.4 mL(5.41 mmol)甲氧基乙醛(自TCI Fine Chemicals公司接收到之批料)及0.46 g三乙醯氧基硼氫化鈉。在室溫下攪拌混合物2小時且接著以15 mL水/1N NaOH水溶液混合物(2/1)稀釋。攪拌所得混合物10分鐘且接著以乙酸乙酯稀釋。經MgSO4 乾燥有機相，過濾且在真空下濃縮。獲得0.41 g對應於7-胺基-2-{4-[1-(2-氯乙基)哌啶-4-基]-2-甲氧基苯基胺基}-8-(2-羥基-2-甲基丙基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺而非最初預期的7-胺基-8-(2-羥基-2-甲基丙基)-2-{2-甲氧基-4-[1-(2-甲氧基乙基)哌啶-4-基]苯基胺基}-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺之黃色固體。產率=69%。To a suspension of 0.60 g (1.08 mmol) of the hydrochloride salt prepared in step 20.7 in 15 mL of anhydrous dichloroethane was added 0.56 mL (3.25 mmol) diisopropylethylamine, 0.4 mL (5.41 mmol) Methoxyacetaldehyde (batch received from TCI Fine Chemicals) and 0.46 g of sodium triethoxysulfonate. The mixture was stirred at room temperature for 2 hours and then diluted with a 15 mL aqueous/1N aqueous NaOH mixture (2/1). The resulting mixture was stirred for 10 minutes and then diluted with ethyl acetate. The organic phase was dried over MgSO 4, filtered and concentrated in vacuo. Obtained 0.41 g corresponding to 7-amino-2-{4-[1-(2-chloroethyl)piperidin-4-yl]-2-methoxyphenylamino}-8-(2-hydroxyl 2-methylpropyl)-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide instead of the originally expected 7-amino-8-(2 -hydroxy-2-methylpropyl)-2-{2-methoxy-4-[1-(2-methoxyethyl)piperidin-4-yl]phenylamino}-5-one A yellow solid of benzyl-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide. Yield = 69%.

22.2：7-胺基-8-(2-羥基-2-甲基丙基)-2-{2-甲氧基-4-[1-(2-甲氧基乙基)哌啶-4-基]苯基胺基}-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺22.2: 7-Amino-8-(2-hydroxy-2-methylpropyl)-2-{2-methoxy-4-[1-(2-methoxyethyl)piperidin-4- Phenylamino}-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide

向0.29 g(0.54 mmol)在步驟22.1中製備的產物於9 mL無水甲醇中之懸浮液中添加0.37 g(2.68 mmol)K2 CO3 ，且使混合物回流1小時。將其蒸發至乾燥且將殘餘物溶解於水及CH2 Cl2 中。經MgSO4 乾燥有機相，過濾且在真空下濃縮。藉由矽膠管柱層析，以二氯甲烷/甲醇梯度(90/10)溶離來純化粗產物。在甲醇中濕磨之後，最終獲得0.22 g呈黃色固體狀之預期產物。產率=78%。0.37 g (2.68 mmol) of K 2 CO 3 was added to a suspension of 0.29 g (0.54 mmol) of the product obtained in step 22.1 in 9 mL of anhydrous methanol, and the mixture was refluxed for 1 hour. Evaporated to dryness and the residue was dissolved in water and the CH 2 Cl 2. The organic phase was dried over MgSO 4, filtered and concentrated in vacuo. The crude product was purified by hydrazine gel column chromatography eluting with dichloromethane/methanol gradient (90/10). After wet milling in methanol, 0.22 g of the desired product was obtained as a yellow solid. Yield = 78%.

22.3：7-胺基-8-(2-羥基-2-甲基丙基)-2-{2-甲氧基-4-[1-(2-甲氧基乙基)哌啶-4-基]苯基胺基}-5-酮基-5,8-二氫吡啶22.3: 7-Amino-8-(2-hydroxy-2-methylpropyl)-2-{2-methoxy-4-[1-(2-methoxyethyl)piperidin-4- Phenylamino}-5-keto-5,8-dihydropyridine 并[2,3-d]嘧啶-6-甲醯胺And [2,3-d]pyrimidine-6-carboxamide

向0.22 g(0.41 mmol)在步驟22.2中製備的產物於8 mL CH2 Cl2 /甲醇混合物(4/1)中之懸浮液中添加1.63 mL(1.63 mmol)1.0 M氫氯醚。在室溫下攪拌混合物5分鐘且接著以***稀釋。藉由抽吸排乾沈澱物，以***及戊烷沖洗並在真空下乾燥。獲得0.23 g呈淡黃色固體狀之預期產物。產率(二鹽酸鹽)=92%。m.p.=170℃(分解)。M+H+ =540To a suspension of 0.22 g (0.41 mmol) of the product obtained in step 22.2 in 8 mL CH 2 Cl 2 / methanol mixture ( 4 / 1) was added 1.63 mL (1.63 mmol) of 1.0 M chloroform ether. The mixture was stirred at room temperature for 5 minutes and then diluted with diethyl ether. The precipitate was drained by suction, rinsed with diethyl ether and pentane and dried under vacuum. Obtained 0.23 g of the expected product as a pale yellow solid. Yield (dihydrochloride) = 92%. Mp = 170 ° C (decomposition). M+H + =540

1 H NMR(DMSO-d6 ,400 MHz):δ11.5(大s,1H);10.35(大s,1H);10.6(m,1H);9.05(s,1H);8.9(s,1H);8.4(大s,1H);7.6(d,1H);7.0(s,1H);6.8(d,1H);4.75(大s,2H);3.7-3.85(m+s,5H);3.6(m,2H);3.2-3.4(m+s,5H);3.1(m,2H);2.85(m,1H);2.15(m,2H);2.0(m,2H);1.0(大s trs,6H)。 1 H NMR (DMSO-d 6 , 400 MHz): δ 11.5 (large s, 1H); 10.35 (large s, 1H); 10.6 (m, 1H); 9.05 (s, 1H); 8.9 (s, 1H) 8.4 (large s, 1H); 7.6 (d, 1H); 7.0 (s, 1H); 6.8 (d, 1H); 4.75 (large s, 2H); 3.7-3.85 (m+s, 5H); 3.6 (m, 2H); 3.2-3.4 (m + s, 5H); 3.1 (m, 2H); 2.85 (m, 1H); 2.15 (m, 2H); 2.0 (m, 2H); 1.0 (large s Tr s, 6H).

實例23：7-胺基-2-[2-甲氧基-4-(1-甲基哌啶-4-基)苯基胺基]-5-酮基-8-苯基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽Example 23: 7-Amino-2-[2-methoxy-4-(1-methylpiperidin-4-yl)phenylamino]-5-one-8-phenyl-5,8 -dihydropyrido[2,3-d]pyrimidin-6-carboxamide hydrochloride

23.1：7-胺基-2-[2-甲氧基-4-(1-甲基哌啶-4-基)苯基胺基]-5-酮基-8-苯基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺23.1:7-Amino-2-[2-methoxy-4-(1-methylpiperidin-4-yl)phenylamino]-5-oneyl-8-phenyl-5,8- Dihydropyrido[2,3-d]pyrimidine-6-carboxamide

將0.2 g(0.55 mmol)在步驟20.5中所獲的碸與亞碸之混合物及0.24 g(1.11 mmol)2-甲氧基-4-(1-甲基哌啶-4-基)苯胺(根據專利WO-09/024 824中所述的方法來製備)在110℃下在5 mL NMP中加熱6小時。在真空下蒸發混合物至乾燥且藉由矽膠管柱層析,以含有痕量濃NH4 OH水溶液之二氯甲烷/甲醇梯度(100/0至95/5)溶離來純化殘餘物。獲得0.096g呈米色固體狀之預期產物。產率=35%。0.2 g (0.55 mmol) of the mixture of hydrazine and hydrazine obtained in step 20.5 and 0.24 g (1.11 mmol) of 2-methoxy-4-(1-methylpiperidin-4-yl)aniline (according to Prepared by the method described in WO-09/024 824) heated in 5 mL of NMP at 110 °C for 6 hours. The mixture was evaporated in vacuo to dryness and by chromatography on silica gel column, methylene chloride containing traces of concentrated NH 4 OH of an aqueous solution / methanol gradient (100/0 to 95/5) The residue was purified fractions. Obtained 0.096 g of the expected product as a beige solid. Yield = 35%.

23.2：7-胺基-2-[2-甲氧基-4-(1-甲基哌啶-4-基)苯基胺基]-5-酮基-8-苯基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽23.2:7-Amino-2-[2-methoxy-4-(1-methylpiperidin-4-yl)phenylamino]-5-keto-8-phenyl-5,8- Dihydropyrido[2,3-d]pyrimidin-6-carboxamide hydrochloride

將0.065 g(0.13 mmol)在步驟23.1中製備的產物於3 mL CH2 Cl2 中之溶液於冰浴上冷卻，且添加0.39 mL(0.39 mmol)氯化氫於***中之1 M溶液。在室溫下攪拌混合物10分鐘且隨後傾入***中。藉由抽吸排乾固體，以戊烷沖洗並在烘箱中在真空下乾燥。獲得0.059 g預期化合物。產率(二鹽酸鹽)=80%。m.p.=256℃(分解)。M+H+ =500The 0.065 g (0.13 mmol) of the product prepared in step 23.1 cooled on 3 mL CH 2 Cl 2 solution in the ice bath, and was added 0.39 mL 1 M solution of diethyl ether (0.39 mmol) in hydrogen chloride. The mixture was stirred at room temperature for 10 minutes and then poured into diethyl ether. The solid was drained by suction, rinsed with pentane and dried under vacuum in an oven. 0.059 g of the expected compound was obtained. Yield (dihydrochloride) = 80%. Mp = 256 ° C (decomposition). M+H + = 500

1 H NMR(DMSO-d6 ,400 MHz):δ11.3(大s,1H);10.25(大s,1H);9.0(s,1H);8.35(s,1H);7.7(m,3H);7.5(m,2H);7.25(大s,1H);7.15(m,1H);6.8(s,1H);6.7(大s,1H);6.3(m,1H);3.8(s,3H);3.45(m,2H);3.0(m,2H);2.8(d,3H);2.7(m,1H);1.85-2.05(m,4H)。 1 H NMR (DMSO-d 6 , 400 MHz): δ 11.3 (large s, 1H); 10.25 (large s, 1H); 9.0 (s, 1H); 8.35 (s, 1H); 7.7 (m, 3H) ); 7.5 (m, 2H); 7.25 (large s, 1H); 7.15 (m, 1H); 6.8 (s, 1H); 6.7 (large s, 1H); 6.3 (m, 1H); 3.8 (s, (3H);

實例24：7-胺基-2-[2-甲氧基-4-(2-吡咯啶-1-基乙基)苯基胺基]-5-酮基-8-苯基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽Example 24: 7-Amino-2-[2-methoxy-4-(2-pyrrolidin-1-ylethyl)phenylamino]-5-oneyl-8-phenyl-5,8 -dihydropyrido[2,3-d]pyrimidin-6-carboxamide hydrochloride

24.1：2-甲氧基-1-硝基-4-乙烯基苯24.1: 2-Methoxy-1-nitro-4-vinylbenzene

在氬氣下將4.32 g(31.31 mmol)三氟乙烯基硼酸鉀及3.12 mL(22.37 mmol)三乙胺添加至5.19 g(22.37 mmol)在步驟4.1中製備的產物於56 mL正丙醇中之混合物中,且鼓入氬氣10分鐘。添加0.36 g(0.45 mmol)PdCl2 dppf‧CH2 Cl2 且在100℃下在氬氣下加熱混合物3小時。在冷卻至室溫之後，濃縮反應混合物至乾燥且接著溶解於二氯甲烷/水混合物中。在藉由沈降分離各相之後，將有機相以水洗滌兩次且以NaCl飽和水溶液洗滌一次。經Na2 SO4 乾燥有機相，過濾且在真空下濃縮。藉由矽膠管柱層析，以環己烷/乙酸乙酯梯度(95/5至70/30)溶離來純化所獲殘餘物。獲得3.1 g呈棕色油狀之預期產物，其按原樣用於下一步中。產率=77%。4.32 g (31.31 mmol) of potassium trifluorovinylborate and 3.12 mL (22.37 mmol) of triethylamine were added under argon to 5.19 g (22.37 mmol) of the product prepared in step 4.1 in 56 mL of n-propanol. The mixture was bubbled with argon for 10 minutes. 0.36 g (0.45 mmol) of PdCl 2 dppf ‧ CH 2 Cl 2 was added and the mixture was heated under argon at 100 ° C for 3 hours. After cooling to room temperature, the reaction mixture was concentrated to dryness and then dissolved in dichloromethane/water mixture. After separating the phases by sedimentation, the organic phase was washed twice with water and once with a saturated aqueous solution of NaCl. Dried over Na 2 SO 4 organic phase was filtered and concentrated in vacuo. The residue obtained was purified by hydrazine gel column chromatography eluting with hexane/ethyl acetate gradient (95/5 to 70/30). 3.1 g of the expected product as a brown oil was obtained which was used in the next step. Yield = 77%.

24.2：1-[2-(3-甲氧基-4-硝基苯基)乙基]吡咯啶24.2: 1-[2-(3-Methoxy-4-nitrophenyl)ethyl]pyrrolidine

將於60 mL無水甲醇中的3.07 g(17.17 mmol)在步驟24.1中製備的產物及7.13 mL(85.84 mL)吡咯啶置於密封管中。在100℃下在壓力下加熱混合物4小時。在冷卻至室溫之後，將其蒸發至乾燥。藉由矽膠管柱層析，以二氯甲烷/甲醇梯度(100/0至90/10)溶離來純化所獲殘餘物。獲得3.22 g呈黃色固體狀之預期產物。產率=75%。3.07 g (17.17 mmol) of the product prepared in step 24.1 and 7.13 mL (85.84 mL) of pyrrolidine in 60 mL of anhydrous methanol were placed in a sealed tube. The mixture was heated under pressure at 100 ° C for 4 hours. After cooling to room temperature, it was evaporated to dryness. The residue obtained was purified by hydrazine gel column chromatography eluting with dichloromethane/methanol gradient (100/0 to 90/10). 3.22 g of the expected product are obtained as a yellow solid. Yield = 75%.

24.3：2-甲氧基-4-(2-吡咯啶-1-基乙基)苯胺24.3: 2-Methoxy-4-(2-pyrrolidin-1-ylethyl)aniline

在氬氣下將0.41 g鈀/木炭及4.1 g(64.32 mmol)甲酸銨添加至3.2 g(12.86 mmol)在步驟24.3中製備的產物於120 mL甲醇中之溶液中，且使混合物回流2小時。在過濾之後，濃縮濾液至乾燥以得到2.6 g呈淡棕色固體狀之預期產物，其按原樣用於下一步中。產率=92%。0.41 g of palladium/charcoal and 4.1 g (64.32 mmol) of ammonium formate were added to a solution of 3.2 g (12.86 mmol) of the product prepared in step 24.3 in 120 mL of methanol under argon, and the mixture was refluxed for 2 hours. After filtration, the filtrate was concentrated to dryness to give 2.6 g of the desired product as pale brown solid. Yield = 92%.

24.4：7-胺基-2-[2-甲氧基-4-(2-吡咯啶-1-基乙基)苯基胺基]-5-酮基-8-苯基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺24.4: 7-Amino-2-[2-methoxy-4-(2-pyrrolidin-1-ylethyl)phenylamino]-5-keto-8-phenyl-5,8- Dihydropyrido[2,3-d]pyrimidine-6-carboxamide

將0.2 g(0.55 mmol)在步驟20.5中所獲的碸與亞碸之混合物及0.24 g(1.11 mmol)在步驟24.3中製備的苯胺在110℃下在5 mL NMP中加熱6小時。在真空下蒸發混合物至乾燥且藉由矽膠管柱層析，以含有痕量濃NH4 OH水溶液之二氯甲烷/甲醇梯度(100/0至90/10)溶離來純化殘餘物。獲得0.07 g呈玻璃質黃色固體狀之預期產物。產率=25%。0.2 g (0.55 mmol) of the mixture of hydrazine and hydrazine obtained in step 20.5 and 0.24 g (1.11 mmol) of the aniline prepared in step 24.3 were heated in 10 mL of NMP at 110 ° C for 6 hours. The mixture was evaporated and dried under vacuum to by silica gel column chromatography, methylene chloride containing a trace of concentrated NH 4 OH of an aqueous solution / methanol gradient (100/0 to 90/10) and the residue was purified fractions. 0.07 g of the expected product was obtained as a glassy yellow solid. Yield = 25%.

24.5：7-胺基-2-[2-甲氧基-4-(2-吡咯啶-1-基乙基)苯基胺基]-5-酮基-8-苯基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺鹽酸鹽24.5: 7-Amino-2-[2-methoxy-4-(2-pyrrolidin-1-ylethyl)phenylamino]-5-keto-8-phenyl-5,8- Dihydropyrido[2,3-d]pyrimidin-6-carboxamide hydrochloride

將0.07 g(0.14 mmol)在步驟24.4中製備的產物於3 mL甲醇中之溶液於冰浴上冷卻，且添加0.42 mL(0.42 mmol)氯化氫於***中之1 M溶液。在室溫下攪拌混合物10分鐘且接著添加***。藉由抽吸排乾固體，以戊烷沖洗並在烘箱中在真空下乾燥。獲得0.075 g預期化合物。產率(二鹽酸鹽)=93%。M+H+ =500A solution of 0.07 g (0.14 mmol) of the product obtained in step 24.4 in 3 mL of MeOH was then evaporated and evaporated. The mixture was stirred at room temperature for 10 minutes and then diethyl ether was added. The solid was drained by suction, rinsed with pentane and dried under vacuum in an oven. 0.075 g of the expected compound was obtained. Yield (dihydrochloride) = 93%. M+H + = 500

1 H NMR(DMSO-d6 +D2O,400 MHz,T=130℃): 9.0(s,1H);7.7(m,3H);7.4(m,2H);7.25(d,1H);6.85(s,1H);6.4(d,1H);3.8(s,3H);3.1-3.5(m,6H);2.9(m,2H);2.0(m,4H)。 1 H NMR (DMSO-d 6 + D 2 O, 400 MHz, T = 130 ° C): 9.0 (s, 1H); 7.7 (m, 3H); 7.4 (m, 2H); 7.25 (d, 1H); s, 1H); 6.4 (d, 1H); 3.8 (s, 3H); 3.1-3.5 (m, 6H); 2.9 (m, 2H); 2.0 (m, 4H).

以下表1說明許多本發明之式(I)化合物的化學結構及物理性質。在此表中：　Me及Et分別表示甲基及乙基，　「LC/UV/MS」行依次表示以下使用及詳述的高效液相層析分析方法(A、B、C或D)、以分鐘表示的化合物之滯留時間(縮寫為tr)及藉由質譜分析所鑑別的MH+ 峰。Table 1 below illustrates the chemical structures and physical properties of a number of compounds of the formula (I) of the present invention. In this table: Me and Et represent methyl and ethyl, respectively. The "LC/UV/MS" row sequentially indicates the HPLC method (A, B, C, or D) used and detailed below, the retention time of the compound expressed in minutes (abbreviated as tr), and mass spectrometry The identified MH + peaks were analyzed.

方法A：Method A:

管柱：Kromasil C18，50×2.1 mm，3.5 μmColumn: Kromasil C18, 50 × 2.1 mm, 3.5 μm

溶劑A：H2 O/ACN/TFA(1000/30/0.5)；溶劑B：ACN/TFA(1000/0.5)；流率=0.5 mL/minSolvent A: H 2 O/ACN/TFA (1000/30/0.5); solvent B: ACN/TFA (1000/0.5); flow rate = 0.5 mL/min

梯度：100/0(0 min)至0/100(12 min)至0/100(15 min)Gradient: 100/0 (0 min) to 0/100 (12 min) to 0/100 (15 min)

偵測：220 nMDetection: 220 nM

電離：ESI+Ionization: ESI+

方法B：Method B:

管柱：Gemini，50×3 mm，3 μmColumn: Gemini, 50 × 3 mm, 3 μm

溶劑A：H2 O+0.1% HCO2 H；溶劑B：ACN+0.1% HCO2 H；流率=1 mL/minSolvent A: H 2 O + 0.1% HCO 2 H; Solvent B: ACN + 0.1% HCO 2 H; flow rate = 1 mL/min

梯度：95/5(0 min)至0/100(5.5 min)至0/100(7.5 min)Gradient: 95/5 (0 min) to 0/100 (5.5 min) to 0/100 (7.5 min)

偵測：220 nMDetection: 220 nM

電離：ESI+Ionization: ESI+

方法C：Method C:

管柱：Kromasil C18，50×2.1 mm，3.5 μmColumn: Kromasil C18, 50 × 2.1 mm, 3.5 μm

溶劑A：CH3 CO2 NH4 5 mM；溶劑B：ACN；流率=0.5 mL/minSolvent A: CH 3 CO 2 NH 4 5 mM; solvent B: ACN; flow rate = 0.5 mL/min

梯度：100/0(0 min)至0/100(13 min)至0/100(16 min)Gradient: 100/0 (0 min) to 0/100 (13 min) to 0/100 (16 min)

偵測：220 nMDetection: 220 nM

電離：ESI+Ionization: ESI+

方法D：Method D:

管柱：Acquity BEH C18，50×2.1 mm；1.7 μmColumn: Acquity BEH C18, 50 × 2.1 mm; 1.7 μm

溶劑A：H2 O+0.05% TFA；溶劑B：ACN+0.035% TFA；流率=1 mL/minSolvent A: H 2 O + 0.05% TFA; solvent B: ACN + 0.035% TFA; flow rate = 1 mL / min

梯度：T0：98% A；T1.6至T2.1 min：100% B；T2.5至T3 min：98%AGradient: T0: 98% A; T1.6 to T2.1 min: 100% B; T2.5 to T3 min: 98% A

偵測：220 nMDetection: 220 nM

電離：EsI+Ionization: EsI+

在「形式」行中，「-」指示化合物呈游離鹼形式，而「HCl」指示化合物呈鹽酸鹽形式，在「化合物」行中，「RAC」指示化合物呈外消旋混合物形式，「」意謂無法獲得數據。 In the "form" row, "-" indicates that the compound is in the form of the free base, and "HCl" indicates that the compound is in the form of the hydrochloride. In the "Compound" row, "RAC" indicates that the compound is in the form of a racemic mixture. " It means that data cannot be obtained.

對本發明化合物進行藥理學試驗以測定其對CaMKIIδ同功異型物之抑制效應。The compounds of the invention were subjected to pharmacological tests to determine their inhibitory effects on CaMKIIδ isoforms.

該等測試係在於量測本發明化合物針對CaMKIIδ之活體外活性。These tests are based on measuring the in vitro activity of the compounds of the invention against CaMKIIδ.

活體外測試本發明化合物抑制鈣/鈣調蛋白依賴性蛋白激酶IIδ(CaMKIIδ)之激酶功能的能力。CaMKIIδ為細胞內絲胺酸/蘇胺酸激酶。其具有能夠使用ATP來自體磷酸化之酶促結構域。其激酶功能使其能使用ATP在絲胺酸及/或蘇胺酸上磷酸化其受質。使用若干酶促及細胞測試來評估產物相關於CaMKIIδ之激酶功能的活性。The ability of the compounds of the invention to inhibit the kinase function of calcium/calmodulin-dependent protein kinase IIδ (CaMKIIδ) was tested in vitro. CaMKIIδ is an intracellular serine/threonine kinase. It has an enzymatic domain that is capable of phosphorylating with ATP. Its kinase function allows it to phosphorylate its substrate on serine and/or threonine using ATP. Several enzymatic and cellular assays were used to assess the activity of the product associated with the kinase function of CaMKIIδ.

藉助於放射性測試針對重組CaMKIIδ酶來評估CaMKIIδ之激酶活性。量測在被CaMKIIδ磷酸化期間ATP-γ33P併入特異性受質Autocamtide-2中的量。用抑制CaMKIIδ總活性達50%的產物濃度(50%抑制濃度=IC50 )來定量產物之效應。為了測定IC50 值，將產物於100% DMSO中稀釋以獲得10 mM儲備溶液。在放射性測試期間所測試的濃度範圍在3至10 000 nM內，在測試中之最終濃度為1% DMSO。對於最有效之化合物而言，此濃度範圍可延伸至0.1 nM。在操作之日，將5 μl化合物以欲測試濃度之10倍的濃度沈積於96孔板之每孔中。在同一板上一式兩份測試各濃度。陰性對照(0%活性)及陽性對照(100%活性)接受5 μL 10% DMSO溶液。製備含有1X激酶緩衝液及ATP-MgCl2 混合物之反應預混物。臨時將含有受質Autocamtide-2(100 μM)與鈣調蛋白及鈣以及酶CaMKIIδ溶液之混合物添加至預混物中。每孔立即沈積45 μL此混合物。在50 μL最終體積中的最終濃度如下：化合物1X、0.37 nM CaMKIIδ(Invitrogen參考文獻PV3373)、10 μM ATP(每孔1 μCi)、100 μM Autocamtide-2、8 μg/mL鈣調蛋白、15 mM MgCl2 、400 μM CaCl2 、10 mMβ-甘油磷酸酯及% DMSO。在各板上製備兩個陰性對照物，第一個不含酶CaMKIIδ，且第二個不含受質Autocamtide-2；以水替代該兩種成分。隨後在37℃下培育該板2小時，伴隨輕微振盪。藉由每孔添加20 μL H3 PO4 溶液來終止反應。將每孔中之50 μL轉移至Whatman P81過濾器上。在以H3 PO4 (每洗滌一次150 μl/孔)沖洗兩次，接著以150 μL H2 O沖洗兩次之後，每孔添加50 μL閃爍體。藉助於液體閃爍計數器偵測磷酸化受質之量。The kinase activity of CaMKIIδ was assessed against recombinant CaMKIIδ enzyme by means of radioactivity testing. The amount of ATP-γ33P incorporated into the specific receptor Autocamtide-2 during phosphorylation by CaMKIIδ was measured. The product concentration inhibiting by 50% CaMKIIδ of total active (50% inhibition concentration = IC 50) to quantify the effect of the product. To determine the 50 value IC, the product is diluted in 100% DMSO to obtain 10 mM stock solution. The concentrations tested during the radioactivity test ranged from 3 to 10 000 nM and the final concentration in the test was 1% DMSO. For the most potent compounds, this concentration range can be extended to 0.1 nM. On the day of the operation, 5 μl of the compound was deposited in each well of a 96-well plate at a concentration 10 times the concentration to be tested. Each concentration was tested in duplicate on the same plate. Negative control (0% active) and positive control (100% active) received 5 μL of 10% DMSO solution. A reaction premix containing 1X Kinase Buffer and ATP-MgCl 2 Mixture was prepared. A mixture containing the substrate Autocamtide-2 (100 μM) and calmodulin and calcium and the enzyme CaMKIIδ solution was temporarily added to the premix. 45 μL of this mixture was deposited immediately per well. Final concentrations in a final volume of 50 μL are as follows: compound 1X, 0.37 nM CaMKIIδ (Invitrogen reference PV3373), 10 μM ATP (1 μCi per well), 100 μM Autocamtide-2, 8 μg/mL calmodulin, 15 mM MgCl 2 , 400 μM CaCl 2 , 10 mM β-glycerophosphate and % DMSO. Two negative controls were prepared on each plate, the first containing no enzyme CaMKIIδ and the second containing no substrate Autocamtide-2; replacing the two components with water. The plate was then incubated at 37 ° C for 2 hours with slight shaking. The reaction was terminated by adding 20 μL of H 3 PO 4 solution per well. Transfer 50 μL of each well to the Whatman P81 filter. After rinsing twice with H 3 PO 4 (150 μl/well per wash), followed by rinsing twice with 150 μL H 2 O, 50 μL of scintillant was added to each well. The amount of phosphorylated receptor is detected by means of a liquid scintillation counter.

用抑制50% CaMKIIδ活性之濃度給出針對CaMKIIδ之抑制活性。IC50 值一般介於10 μM與10-5 μM之間。在下表中，呈現對若干本發明化合物(I)所量測之IC50 值作為實例。The inhibitory activity against CaMKIIδ was given by the concentration which inhibited 50% CaMKIIδ activity. The IC 50 value is typically between 10 μM and 10 -5 μM. In the following table, IC 50 values measured for several compounds (I) of the present invention are shown as an example.

由此可見，本發明化合物對CaMKIIδ具有抑制活性。From this, it can be seen that the compound of the present invention has an inhibitory activity against CaMKIIδ.

本發明化合物因此可用於製備抑制CaMKII之藥劑且尤其抑制CaMKIIδ之藥劑。The compounds of the invention are therefore useful in the preparation of agents which inhibit CaMKII and in particular inhibit CaMKIIδ.

因此，根據其另一態樣，本發明之目標為藥劑，其包含式(I)化合物、或其與醫藥學上可接受之酸形成的加成鹽、或者式(I)化合物之水合物或溶劑合物。Thus, according to another aspect thereof, the object of the invention is an agent comprising a compound of formula (I), or an addition salt thereof with a pharmaceutically acceptable acid, or a hydrate of a compound of formula (I) or Solvate.

此等藥劑可用於療法中，尤其用於治療及/或預防涉及CaMKII且尤其涉及CaMKIIδ之病變。Such agents are useful in therapy, particularly for the treatment and/or prevention of lesions involving CaMKII and, in particular, CaMKIIδ.

根據其另一態樣，本發明亦係關於式(I)化合物之用途，其係用於製備藥劑，該藥劑係用於預防及/或治療：心血管病變，包括心肌梗塞、心室肥大、心肌纖維化、心機能不全、心律不整及再狹窄，以及與包括肝纖維化、胰纖維化、腎纖維化、肺纖維化、皮膚纖維化、腸纖維化及眼部纖維化之纖維化發展相關的病變。式(I)化合物亦可用於治療及/或預防諸如急性腎功能不全之其他腎病變，以及治療動脈粥樣硬化、類風濕性關節炎、帕金森氏症及中風。According to another aspect thereof, the invention also relates to the use of a compound of formula (I) for the preparation of a medicament for the prevention and/or treatment of cardiovascular diseases, including myocardial infarction, ventricular hypertrophy, myocardial Fibrosis, cardiac insufficiency, arrhythmia and restenosis, and associated with fibrosis including liver fibrosis, pancreatic fibrosis, renal fibrosis, pulmonary fibrosis, skin fibrosis, intestinal fibrosis, and ocular fibrosis Lesion. The compounds of formula (I) are also useful in the treatment and/or prevention of other renal disorders such as acute renal insufficiency, as well as in the treatment of atherosclerosis, rheumatoid arthritis, Parkinson's disease and stroke.

根據其另一態樣，本發明係關於醫藥組合物，其包含本發明化合物作為活性成分。此等醫藥組合物含有有效劑量之至少一種本發明化合物，或該化合物之醫藥學上可接受之鹽、水合物或溶劑合物，以及至少一種醫藥學上可接受之賦形劑。According to another aspect thereof, the present invention relates to a pharmaceutical composition comprising a compound of the present invention as an active ingredient. These pharmaceutical compositions contain an effective amount of at least one compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate of the compound, and at least one pharmaceutically acceptable excipient.

根據醫藥形式及所需投藥方式，自熟習此項技術者已知之常用賦形劑中選擇該等賦形劑。These excipients are selected from the usual excipients known to those skilled in the art depending on the form of the drug and the mode of administration desired.

在適於經口、舌下、皮下、肌肉內、靜脈內、表皮(topical)、局部(local)、氣管內、鼻內、經皮或直腸投藥之本發明醫藥組合物中，以上式(I)之活性成分或其可能的鹽、溶劑合物或水合物可作為與標準醫藥賦形劑之混合物以單位投藥形式投與男性及動物，以便預防或治療上述病症或疾病。In the pharmaceutical composition of the present invention suitable for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the above formula (I) The active ingredient or a possible salt, solvate or hydrate thereof can be administered to a male or an animal in a unit dosage form as a mixture with a standard pharmaceutical excipient to prevent or treat the above-mentioned condition or disease.

適當單位投藥形式包括口服形式，諸如錠劑、軟或硬凝膠膠囊、散劑、顆粒及口服溶液或懸浮液；舌下、頰內、氣管內、眼內、鼻內或吸入投藥形式；表皮、經皮、皮下、肌肉內或靜脈內投藥形式；直腸投藥形式及植入物形式。對於表皮施用而言，本發明化合物可以乳膏、凝膠、軟膏或洗劑形式使用。Suitable unit dosage forms include oral forms such as lozenges, soft or hard gelatin capsules, powders, granules and oral solutions or suspensions; sublingual, buccal, intratracheal, intraocular, intranasal or inhaled administration; epidermis, Transdermal, subcutaneous, intramuscular or intravenous administration; rectal administration and implant form. For epidermal administration, the compounds of the invention may be used in the form of a cream, gel, ointment or lotion.

舉例而言，呈錠劑形式的本發明化合物之單位投藥形式可包含以下組份：For example, a unit dosage form of a compound of the invention in the form of a tablet may comprise the following ingredients:

本發明化合物　50.0 mgInventive Compound 50.0 mg

甘露糖醇　223.75 mgMannitol 223.75 mg

交聯羧甲纖維素鈉　6.0 mgCroscarmellose sodium 6.0 mg

玉米澱粉　15.0 mgCorn Starch 15.0 mg

羥丙基甲基纖維素　2.25 mgHydroxypropyl methylcellulose 2.25 mg

硬脂酸鎂　3.0 mgMagnesium stearate 3.0 mg

可能存在較高或較低劑量為適宜的特殊情況；該等劑量並未超出本發明之範疇。根據慣例，各患者之適用劑量由醫生根據投藥方式及該患者之體重及反應來確定。There may be special cases where higher or lower doses are suitable; such doses are not beyond the scope of the invention. In accordance with established practice, the appropriate dosage for each patient is determined by the physician based on the mode of administration and the weight and response of the patient.

根據其另一態樣，本發明亦係關於一種治療及/或預防上述病變之方法，其包含將有效劑量之本發明化合物或其醫藥學上可接受之鹽或水合物或溶劑合物投與患者。According to another aspect thereof, the present invention relates to a method of treating and/or preventing the above-mentioned lesion comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt or hydrate or solvate thereof. patient.

Claims (26)

一種對應於通式(I)之化合物， 其中：A表示CH或C(C1 -C6 烷基)；X 表示CH，C(C1 -C6 烷基)或N；R 1 、R 2 、R 3 及R 4 可相同或不同，彼此獨立地表示：氫原子，直鏈或分支鏈C1 -C6 烷基或C3 -C6 環烷基，視情況經一或多個下列基團取代：鹵素原子，-OR9 ，-NR9 R'9 ，-CN，-C(O)OR9 ，-C(O)NR9 R9' ，-S(O)p R10 ，-S(O)2 NR9 R'9 ，其中R 9 、R' 9 、R 10 及p 如下定義，基團-S(O)p R10 ，其中p及R10 如下定義， 基團-OR10 ，其中R10 如下定義，鹵素原子，基團-N(R11 )C(O)R12 ，其中(iii)R 11 及R 12 彼此獨立地表示氫原子，或直鏈或分支鏈C1 -C6 烷基或C3 -C6 環烷基，視情況經一或多個選自鹵素原子、基團-OR9 及基團-NR9 R'9 之取代基取代，或(iv)R 11 及R 12 與其所連接之原子一起形成內醯胺，基團-N(R14 )-CH2 -C(O)NR15 R9 ，其中R 14 及R 15 與其所連接之原子一起形成哌嗪酮且其中R 9 如下定義，基團-C(O)NR16 R17 ，其中R 16 及R 17 與其所連接之氮原子一起形成哌啶基或吡咯啶基，基團-T-U ，其中：T 表示：單鍵，直鏈或分支鏈C1 -C6 伸烷基，基團-C(O)-，基團-S(O)p -，其中p如下定義，或基團-O-(CH2 )n -，其中n如下定義，且U 表示雜環烷基或雜芳基，視情況經1、2或數個選自以下之取代基單取代或二取代或多取代：基團-OR7 ，其中R7 如下定義，鹵素原子， 基團-C(O)R7 ，其中R7 如下定義，直鏈或分支鏈C1 -C6 烷基或C3 -C6 環烷基，視情況經一或多個選自鹵素原子、基團-OR10 、基團-NR9 R'9 及基團-CN之取代基取代，其中R9 、R'9 及R10 如下定義，及雜環烷基或雜芳基，視情況經一或多個選自鹵素原子、基團-OR9 、基團-NR9 R'9 及C1 -C6 烷基之取代基取代，該等C1 -C6 烷基視情況經一或多個鹵素原子取代，或T 表示：基團-C(O)-，基團-S(O)2 -，或基團-O-(C2 -C3 )伸烷基-，且U表示基團-NR9 R'9 ，其中R9 及R'9 如下定義，或T 表示：基團-C(O)-，或基團-O-(C2 -C3 )伸烷基-，且U 表示基團-OR9 ，其中R9 如下定義，或T 表示：直鏈或分支鏈C1 -C6 伸烷基，或基團-O-(C2 -C3 )伸烷基-，且U 表示基團-NR8 R9 ，其中R9 及R8 如下定義；或者選自R 1 、R 2 、R 3 及R 4 之兩個相鄰基團與攜帶彼等之兩個碳連接並形成雜環烷基或雜芳基，視情況經一 或多個直鏈或分支鏈C1 -C6 烷基或C3 -C6 環烷基取代，該等C1 -C6 烷基或C3 -C6 環烷基視情況經一或多個選自鹵素原子、基團-OR10 及基團-NR9 R'9 之取代基取代，其中R9 、R'9 及R10 如下定義，該雜環烷基或雜芳基係與芳族環稠合；R 5 表示：直鏈或分支鏈C1 -C6 烷基，視情況經一或多個選自下列之取代基取代：鹵素原子、基團-OR9 、基團-NR9 R'9 、基團-CN、基團-C(O)NR9 R9' 、基團-S(O)p R10 及視情況經基團-NR9 R'9 取代之C3 -C6 環烷基，其中R9 、R'9 、R10 及p如下定義，C3 -C6 環烷基，視情況經基團-NR9 R'9 取代，其中R9 及R'9 如下定義，C1 -C6 烷氧基-OR9 ，其中R9 如下定義，芳基，視情況經一或多個選自基團(C1 -C3 )烷基、鹵素原子及基團-O-(C1 -C3 )烷基之取代基取代，或基團-(CH2 )t -R13 ，其中R 1 3 及t 如下定義；R 6 表示氫原子，或直鏈或分支鏈C1 -C6 烷基或C3 -C6 環烷基，且其中：R 7 表示氫原子，或視情況經一或多個選自以下之取代基取代的直鏈或分支鏈C1 -C6 烷基或C3 -C6 環烷基：鹵素原子、基團-OR9 及基團-NR9 R'9 ，其中R9 及R'9 如下定義；R 8 表示雜芳基；R 9 及R' 9 彼此獨立地表示氫原子或直鏈或分支鏈C1 -C6 烷基或C3 -C6 環烷基；R 10 表示 氫原子或視情況經一或多個鹵素原子取代之直鏈或分支鏈C1 -C6 烷基或C3 -C6 環烷基；R 13 表示視情況 經一或多個選自直鏈或分支鏈C1 -C6 烷基或C3 -C6 環烷基之取代基取代的雜芳基或雜環烷基，應瞭解當該雜環烷基包含至少一個氮原子時，此原子可視情況攜帶該取代基；t 表示1或2；n 表示0、1、2或3；及p 表示0、1或2；其中該雜環烷基意指包含一或多個選自O、N及S之雜原子的3員至10員單環或雙環基團，其可為飽和的或部分不飽和的且可包含一或多個雙鍵；該芳基意指包含5至10個碳原子之單環或雙環芳族基；該雜環意指包含1、2或3個選自O、N及S之雜原子且為芳族的5員至10員環狀基；呈酸、鹼、或與酸或鹼之加成鹽形式。a compound corresponding to the formula (I), Wherein: A represents CH or C(C 1 -C 6 alkyl); X represents CH, C(C 1 -C 6 alkyl) or N; R 1 , R 2 , R 3 and R 4 may be the same or different, Independently from each other: a hydrogen atom, a straight or branched C 1 -C 6 alkyl group or a C 3 -C 6 cycloalkyl group, optionally substituted with one or more of the following groups: a halogen atom, -OR 9 ,- NR 9 R' 9 , -CN, -C(O)OR 9 , -C(O)NR 9 R 9' , -S(O) p R 10 , -S(O) 2 NR 9 R' 9 , wherein R 9 , R' 9 , R 10 and p are as defined below, the group -S(O) p R 10 , wherein p and R 10 are as defined below, the group -OR 10 , wherein R 10 is as defined below, a halogen atom, a group -N(R 11 )C(O)R 12 , wherein (iii) R 11 and R 12 independently of each other represent a hydrogen atom, or a linear or branched C 1 -C 6 alkyl group or a C 3 -C 6 naphthenic group a group, optionally substituted with one or more substituents selected from a halogen atom, a group -OR 9 and a group -NR 9 R' 9 or (iv) R 11 and R 12 together with the atom to which they are attached Indoleamine, a group -N(R 14 )-CH 2 -C(O)NR 15 R 9 , wherein R 14 and R 15 together with the atom to which they are attached form a piperazinone wherein R 9 is as defined below, group - C(O)NR 16 R 17 , wherein R 16 and R 1 7 together with the nitrogen atom to which it is attached form a piperidinyl or pyrrolidinyl group, the group -TU , wherein: T represents: a single bond, a straight or branched chain C 1 -C 6 alkyl group, a group -C(O -, a group -S(O) p -, wherein p is as defined below, or the group -O-(CH 2 ) n -, wherein n is as defined below, and U represents a heterocycloalkyl or heteroaryl group, as appropriate Monosubstituted or disubstituted or polysubstituted with 1, 2 or several substituents selected from the group consisting of -OR 7 wherein R 7 is as defined below, a halogen atom, a group -C(O)R 7 , wherein R 7 A straight-chain or branched C 1 -C 6 alkyl group or a C 3 -C 6 cycloalkyl group, as the case may be optionally one or more selected from the group consisting of a halogen atom, a group -OR 10 , a group -NR 9 R' 9 and the group of -CN substituents, wherein R 9, R '9 and R 10 as defined below, and heterocycloalkyl or heteroaryl, optionally substituted with one or more substituents selected from a halogen atom, a group -OR 9, the group -NR 9 R '9 and the C 1 -C 6 alkyl substituents, such C 1 -C 6 alkyl optionally substituted with one or more halogen atoms, or T represents: a group - C (O) -, a group -S (O) 2 -, or a group -O- (C 2 -C 3) alkylene -, and U represents a group -NR 9 R '9, which R 9 and R '9 are defined as follows, or T represents: the group -C (O) -, or a group -O- (C 2 -C 3) alkylene -, and U represents a group -OR 9, wherein R 9 is as defined below, or T represents: a linear or branched C 1 -C 6 alkyl group, or a group -O-(C 2 -C 3 )alkyl-, and U represents a group -NR 8 R 9 wherein R 9 and R 8 are as defined below; or two adjacent groups selected from the group consisting of R 1 , R 2 , R 3 and R 4 are bonded to two carbons carrying the same and form a heterocycloalkyl or heteroaryl group a group, optionally substituted by one or more straight or branched C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl groups, such C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl Substituting one or more substituents selected from the group consisting of a halogen atom, a group -OR 10 and a group -NR 9 R' 9 wherein R 9 , R' 9 and R 10 are as defined below, or a heterocycloalkyl group or The heteroaryl is fused to an aromatic ring; R 5 represents a straight or branched C 1 -C 6 alkyl group, optionally substituted with one or more substituents selected from the group consisting of a halogen atom, a group-OR 9 , a group -NR 9 R' 9 , a group -CN, a group -C(O)NR 9 R 9' , a group -S(O) p R 10 and optionally a group -NR 9 R' 9 substituted C 3 -C 6 cycloalkyl, wherein R 9 , R' 9 , R 10 and p are as defined below, C 3 -C 6 cycloalkyl, optionally substituted by the group -NR 9 R' 9 wherein R 9 and R' 9 are as defined below, C 1 -C 6 alkane Oxy-OR 9 , wherein R 9 is as defined below, aryl, optionally, one or more selected from the group consisting of a (C 1 -C 3 )alkyl group, a halogen atom and a group -O-(C 1 -C 3 a substituent substituted with an alkyl group, or a group -(CH 2 ) t -R 13 wherein R 1 3 and t are as defined below; R 6 represents a hydrogen atom, or a straight or branched C 1 -C 6 alkyl group or C 3 -C 6 cycloalkyl, and wherein: R 7 represents a hydrogen atom, or optionally a linear or branched C 1 -C 6 alkyl group or C 3 - substituted with one or more substituents selected from the group consisting of: C 6 cycloalkyl: a halogen atom, a group -OR 9 and a group -NR 9 R' 9 , wherein R 9 and R' 9 are as defined below; R 8 represents a heteroaryl group; R 9 and R' 9 are independently of each other And represents a hydrogen atom or a linear or branched C 1 -C 6 alkyl group or a C 3 -C 6 cycloalkyl group; R 10 represents a hydrogen atom or a linear or branched chain C 1 substituted with one or more halogen atoms as the case may be. -C 6 alkyl or C 3 -C 6 cycloalkyl group; R 13 represents optionally substituted with one or more substituents selected from a straight-chain or branched C 1 -C 6 alkyl or C 3 -C 6 The substituted alkyl group, or substituted heteroaryl heterocycloalkyl, heterocycloalkyl should be understood that when the alkyl group contains at least one nitrogen atom, this atom may optionally carrying the substituents; T represents 1 or 2; n represents 0, 1, 2 or 3; and p represents 0, 1 or 2; wherein the heterocycloalkyl means a 3- to 10-membered monocyclic or bicyclic group containing one or more heteroatoms selected from O, N and S; , which may be saturated or partially unsaturated and may contain one or more double bonds; the aryl group means a monocyclic or bicyclic aromatic group containing 5 to 10 carbon atoms; 2 or 3 ring members of 5 to 10 members which are heteroatoms selected from O, N and S and which are aromatic; in the form of an acid, a base or an addition salt with an acid or a base. 如請求項1之化合物，其特徵在於：A 表示CH或C(CH3 )；及/或X 表示CH或N。The compound of claim 1, wherein: A represents CH or C(CH 3 ); and/or X represents CH or N. 如請求項1或2之化合物，其特徵在於：A 表示CH；X 表示CH，C(C1 -C6 烷基)或N；R 1 、R 2 、R 3 及R 4 可相同或不同，彼此獨立地表示：氫原子，直鏈或分支鏈C1 -C6 烷基或C3 -C6 環烷基，視情況經一或多個下列基團取代：鹵素原子、基團-OR9 或-NR9 R'9 ，其中R9 及R'9 彼此獨立地表示氫原子，或直鏈或分支鏈C1 -C6 烷基或C3 -C6 環烷基，基團-S(O)p R10 或基團-OR10 ，其中R10 表示氫原子或視情況經一或多個鹵素原子取代的直鏈或分支鏈C1 -C6 烷基或C3 -C6 環烷基，且p表示0、1或2，鹵素原子，基團-N(R11 )C(O)R12 ，其中R11 及R12 彼此獨立地表示氫原子或直鏈或分支鏈C1 -C6 烷基或C3 -C6 環烷基，或R11 及R12 與其所連接之原子一起形成內醯胺，基團-T-U ，其中T 表示：單鍵，直鏈或分支鏈C1 -C6 伸烷基，基團-C(O)-，基團-S(O)p ，其中p表示0、1或2，基團-O-(CH2 )n -，其中n表示0、1、2或3，且U 表示具有下式之雜環烷基或雜芳基： 其中*表示U連接至T之位置，M1 表示C或N原子，M2 及M3 可相同或不同，表示C、N或O原子或S(O)p，其中p=0、1或2，M4 表示C、C(=O)、N、O或S(O)p原子，其中p=0、1或2，各Mi 可相同或不同，表示C、C(=O)、N、O或S(O)p原子，其中p=0、1或2，i =0、1、2或3，應瞭解在適當時若價數可行及/或相鄰M1、M2、M3、M4或Mi可經由雙鍵連接，則該M1、M2、M3、M4或Mi各可視情況經取代，該U 係視情況經1、2或數個選自以下之取代基單取代或二取代或多取代：基團-OR7 ，其中R7 表示氫原子，或直鏈或分支鏈C1 -C6 烷基或C3 -C6 環烷基，鹵素原子，基團-COR7 ，其中R7 表示氫原子或直鏈或分支鏈C1 -C6 烷基或C3 -C6 環烷基，直鏈或分支鏈C1 -C6 烷基或C3 -C6 環烷基，視情況經一或多個鹵素原子取代， 雜環烷基或雜芳基；或者，R 1 、R 2 、R 3 及R 4 中的兩個相鄰基團與攜帶彼等之兩個碳連接並形成雜環烷基或雜芳基，視情況經一或多個直鏈或分支鏈C1 -C6 烷基或C3 -C6 環烷基取代，該等C1 -C6 烷基及C3 -C6 環烷基視情況經至少一個選自基團-NR9 R'9 之基團取代，其中R9 及R'9 彼此獨立地表示氫原子或C1 -C6 烷基，該雜環烷基或雜芳基係與芳環稠合。The compound of claim 1 or 2, wherein: A represents CH; X represents CH, C(C 1 -C 6 alkyl) or N; and R 1 , R 2 , R 3 and R 4 may be the same or different, Independently from each other: a hydrogen atom, a straight or branched C 1 -C 6 alkyl group or a C 3 -C 6 cycloalkyl group, optionally substituted with one or more of the following groups: a halogen atom, a group -OR 9 Or -NR 9 R' 9 , wherein R 9 and R' 9 independently of each other represent a hydrogen atom, or a linear or branched C 1 -C 6 alkyl group or a C 3 -C 6 cycloalkyl group, a group -S ( O) p R 10 or a group -OR 10 , wherein R 10 represents a hydrogen atom or, as the case may be, a straight or branched C 1 -C 6 alkyl group or a C 3 -C 6 naphthenic group substituted by one or more halogen atoms And p represents 0, 1 or 2, a halogen atom, a group -N(R 11 )C(O)R 12 , wherein R 11 and R 12 independently of each other represent a hydrogen atom or a straight or branched chain C 1 - C 6 alkyl or C 3 -C 6 cycloalkyl, or R 11 and R 12 together with the atom to which they are attached form an indoleamine, a group -TU , wherein T represents: a single bond, a straight or branched chain C 1 -C 6 alkylene, the group -C (O) -, a group -S (O) p, wherein p represents 0, 1 or 2, a group -O- (CH 2) n -, wherein n represents 0 1, 2 or 3, and U represents a group having the formula of heterocyclic or heteroaryl group: Where * indicates that U is attached to the position of T, M1 represents C or N atoms, and M2 and M3 may be the same or different, representing C, N or O atoms or S(O)p, where p=0, 1 or 2, M4 represents C, C (= O), N, O or S (O) p atom, where p = 0, 1 or 2, each Mi may be the same or different, indicating C, C (= O), N, O or S ( O) p atom, where p = 0, 1 or 2, i = 0, 1, 2 or 3, it should be understood that if appropriate, if the valence is feasible and / or adjacent M1, M2, M3, M4 or Mi can be doubled When the bond is bonded, the M1, M2, M3, M4 or Mi may be optionally substituted, and the U is optionally monosubstituted or disubstituted or polysubstituted by 1, 2 or several substituents selected from the group consisting of: OR 7 , wherein R 7 represents a hydrogen atom, or a linear or branched C 1 -C 6 alkyl group or a C 3 -C 6 cycloalkyl group, a halogen atom, a group -COR 7 , wherein R 7 represents a hydrogen atom or a straight a chain or branched chain C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, straight or branched C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, optionally one or more substituted with a halogen atom, heterocycloalkyl or heteroaryl; or, R 1, R 2, R 3 and R 4 carrying two adjacent groups of two carbons are connected to form a heterocyclic their An aryl group or heteroaryl group, optionally substituted with one or more straight-chain or branched C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl such and C 3 -C The 6 cycloalkyl group is optionally substituted with at least one group selected from the group -NR 9 R' 9 wherein R 9 and R' 9 independently of each other represent a hydrogen atom or a C 1 -C 6 alkyl group, the heterocycloalkane The aryl or heteroaryl is fused to the aromatic ring. 如請求項3之化合物，其中U係視情況經1、2或多個選自以下之取代基單-、二-或多取代：含N雜環烷基或雜芳基，其係視情況經1或多個選自以下之取代基取代：鹵素原子、及視情況經1或多個鹵素原子取代之C1 -C6 烷基與C3 -C6 環烷基。The compound of claim 3, wherein U is optionally mono-, di- or polysubstituted by 1, 2 or more substituents selected from the group consisting of N-heterocycloalkyl or heteroaryl, as appropriate One or more substituents selected from the group consisting of a halogen atom, and optionally a C 1 -C 6 alkyl group substituted with one or more halogen atoms, and a C 3 -C 6 cycloalkyl group. 如請求項1或2之化合物，其特徵在於對應於下式(I')： 其中：R 1 表示：氫原子，直鏈或分支鏈C1 -C6 烷基或C3 -C6 環烷基，視情況經一或多個選自以下之取代基取代：鹵素原子、基團- NR9 R'9 ，其中R9 及R'9 彼此獨立地表示氫原子或C1 -C6 烷基，-OR10 ，其中R10 表示氫原子，或視情況經一或多個鹵素原子取代之直鏈或分支鏈C1 -C6 烷基或C3 -C6 環烷基，鹵素原子，基團-T-U ，其中T 表示：單鍵，C1 -C6 伸烷基，基團-C(O)-，基團-O-(CH2 )n -，其中n表示0、1、2或3，且U 表示視情況經一取代基單取代或二取代的雜環烷基或雜芳基；R 2 、R 3 及R 4 可相同或不同，獨立地表示：氫原子，直鏈或分支鏈C1 -C6 烷基或C3 -C6 環烷基，視情況經一或多個選自以下之取代基取代：鹵素原子及基團-NR9 R'9 ，其中R9 及R'9 彼此獨立地表示氫原子或C1 -C6 烷基，基團-OR10 ，其中R10 表示氫原子或視情況經一或多個鹵素原子取代之C1 -C6 烷基，鹵素，基團-T-U，其中T表示一鍵且U表示嗎啉基；或R 1 及R 2 與攜帶其之兩個碳原子連接並形成雜環烷基，選自哌啶、噻唑、四氫呋喃及二噁烷，該雜環烷基視情況經直鏈或分支鏈C1 -C6 烷基或C3 -C6 環烷基取代，該直鏈或分支鏈C1 -C6 烷基或C3 -C6 環烷基視情況經-NR9 R'9 取代，其中R9 及R'9 彼此獨立地表示氫原子或甲基，該雜環烷基係與芳環稠合；R 5 表示(i)包含1至5個碳原子之直鏈或分支鏈C1 -C6 烷基或C3 -C6 環烷基，視情況經一或多個選自鹵素原子或基團-OH之取代基取代，(ii)芳基，視情況經一或多個選自基團(C1 -C3 )烷基、鹵素原子及基團-O-(C1 -C3 )烷基之取代基取代；呈酸、鹼、或與酸或鹼之加成鹽形式。A compound according to claim 1 or 2, which is characterized in that it corresponds to the following formula (I'): Wherein: R 1 represents: a hydrogen atom, a linear or branched C 1 -C 6 alkyl group or a C 3 -C 6 cycloalkyl group, optionally substituted with one or more substituents selected from the group consisting of halogen atoms, radicals -NR 9 R' 9 , wherein R 9 and R' 9 independently of each other represent a hydrogen atom or a C 1 -C 6 alkyl group, -OR 10 , wherein R 10 represents a hydrogen atom or, as the case may be, one or more halogen Atom-substituted straight or branched C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, halogen atom, group -TU , wherein T represents: a single bond, C 1 -C 6 alkyl, base a group -C(O)-, a group -O-(CH 2 ) n -, wherein n represents 0, 1, 2 or 3, and U represents a heterocycloalkyl group which is optionally substituted or disubstituted with a substituent. Or a heteroaryl group; R 2 , R 3 and R 4 may be the same or different and independently represent a hydrogen atom, a linear or branched C 1 -C 6 alkyl group or a C 3 -C 6 cycloalkyl group, as the case may be. Substituted with one or more substituents selected from the group consisting of a halogen atom and a group -NR 9 R' 9 , wherein R 9 and R' 9 independently of each other represent a hydrogen atom or a C 1 -C 6 alkyl group, a group-OR 10, where R 10 represents a hydrogen atom or optionally substituted with one or more of halogen atoms, C 1 -C 6 alkyl Halo, -TU group, where T represents a bond and U represents a morpholino group; or R 1 and R 2 carries two of its carbon atom to form a heterocyclic group and selected from piperidine, thiazole, tetrahydrofuran and Dioxane, which is optionally substituted by a linear or branched C 1 -C 6 alkyl group or a C 3 -C 6 cycloalkyl group, which is a linear or branched C 1 -C 6 alkyl group or C The 3- C 6 cycloalkyl group is optionally substituted by -NR 9 R' 9 , wherein R 9 and R' 9 independently of each other represent a hydrogen atom or a methyl group, and the heterocycloalkyl group is fused to an aromatic ring; R 5 represents (i) a linear or branched C 1 -C 6 alkyl group or a C 3 -C 6 cycloalkyl group having 1 to 5 carbon atoms, optionally one or more selected from a halogen atom or a group -OH Substituent substitution, (ii) aryl, optionally substituted by one or more selected from the group consisting of (C 1 -C 3 )alkyl, halogen atom and group -O-(C 1 -C 3 )alkyl Substituent; in the form of an acid, a base, or an addition salt with an acid or a base. 如請求項1或2之化合物，其特徵在於：A 表示CH；及/或X 表示CH；及/或R 1 不為氫原子；及/或R 5 表示直鏈或分支鏈C1 -C6 烷基或C3 -C6 環烷基；及/或U 表示雜環烷基或雜芳基，視情況經單取代或二取代，包含至少一個氮原子及/或一個氧原子，及/或U 表示包含至少一個氮原子之雜環烷基或雜芳基，及/或U 表示選自以下之雜環烷基：氮雜環丁烷基，吡咯啶基， 酮基吡咯啶基(oxopyrrolidinyl)，哌啶基，1,2,3,6-四氫吡啶基，吡啶基，哌嗪基，二氮雜環庚烷基(diazepanyl)，嗎啉基，1,1-二酮基(dioxo)-1λ6-硫嗎啉-4-基。A compound according to claim 1 or 2, wherein: A represents CH; and/or X represents CH; and/or R 1 is not a hydrogen atom; and/or R 5 represents a straight or branched chain C 1 -C 6 An alkyl or C 3 -C 6 cycloalkyl group; and/or U represents a heterocycloalkyl or heteroaryl group, optionally substituted or disubstituted, containing at least one nitrogen atom and/or one oxygen atom, and/or U represents a heterocycloalkyl or heteroaryl group containing at least one nitrogen atom, and/or U represents a heterocycloalkyl group selected from the group consisting of azetidinyl, pyrrolidinyl, oxopyrrolidinyl. , piperidinyl, 1,2,3,6-tetrahydropyridyl, pyridyl, piperazinyl, diazepyl, morpholinyl, 1,1-dione (dioxo) -1λ6-thiomorpholin-4-yl. 如請求項1或2之化合物，其特徵在於R 1 係選自： (其中p=0、1、2或3)、、 A compound according to claim 1 or 2, characterized in that R 1 is selected from the group consisting of: (where p=0, 1, 2 or 3), , 如請求項1或2之化合物，其特徵在於A 及X 表示CH。 A compound according to claim 1 or 2, characterized in that A and X represent CH. 如請求項1或2之化合物，其特徵在於U 表示包含至少一個氮原子之飽和雜環。A compound according to claim 1 or 2, characterized in that U represents a saturated heterocyclic ring containing at least one nitrogen atom. 如請求項1或2之化合物，其特徵在於其係選自：7-胺基-8-乙基-2-(4-羥基苯基胺基)-5-酮基(oxo)-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(苯并噻唑-6-基胺基)-8-乙基-5-酮基-5,8-二 氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[4-(環丙烷羰基甲基胺基)苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(4-甲基哌嗪-1-羰基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(4-環戊氧基苯基胺基)-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(4-乙基哌嗪-1-基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-[4-(4-吡咯啶-1-基哌啶-1-基)苯基胺基]-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-[4-(4-吡咯啶-1-基哌啶-1-基)苯基胺基]-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-[4-(4-吡咯啶-1-基哌啶-1-基)苯基胺基]-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-環戊基-2-(4-嗎啉-4-基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-[4-(哌啶-1-磺醯基)苯基胺基]-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；2-[4-(4-乙醯基哌嗪-1-基)苯基胺基]-7-胺基-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-(4-嗎啉-4-基苄基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-(喹啉-3-基胺基)-5,8-二氫吡 啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-[4-(3-哌啶-1-基丙氧基)苯基胺基]-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-(3,4,5,6-四氫-2H-[1,2']聯吡啶-5'-基胺基)-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-[4-(2-酮基吡咯啶-1-基)苯基胺基]-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-(喹啉-6-基胺基)-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-(3-嗎啉-4-基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(2,3-二氫苯并[1,4]二氧雜環己烯(dioxin)-6-基胺基)-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-(3-氟-4-羥基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-(3-甲基硫基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-(4-嗎啉-4-基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-(4-嗎啉-4-基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-(4-嗎啉-4-基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺； 7-胺基-8-乙基-2-(2-氟苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[4-(4,4-二氟[1,4']聯哌啶-1'-基)-2-甲氧基苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[2-甲氧基-4-(4-三氟甲基[1,4']聯哌啶-1'-基)苯基胺基]5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-{4-[4-(3,3-二氟吡咯啶-1-基)哌啶-1-基]-2-甲氧基苯基胺基}-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(4-乙基哌嗪-1-基)-2-氟-6-甲氧基苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[4-(1-環丙基哌啶-4-基)-2-甲氧基苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(2-二甲基胺基甲基烷-6-基胺基)-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[5-氯-4-(4-環丙基哌嗪-1-基)-2-甲氧基苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[2-甲氧基-4-(4-嗎啉-4-基哌啶-1-基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺； 7-胺基-2-[4-(4-環丙基哌嗪-1-基)-2-二氟甲氧基苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[4-(4-環丙基哌嗪-1-基)-2-甲氧基苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[2-氯-4-(4-乙基哌嗪-1-基)苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(4-乙基哌嗪-1-基)-3-三氟甲基苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-(4-嗎啉-4-基甲基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-{4-[4-(3,3,3-三氟丙基)哌嗪-1-基]苯基胺基}-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(4-乙基哌嗪-1-基)-3-氟苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；6-(4-嗎啉-4-基苯基胺基)-9-酮基-1,3,4,9-四氫-2H-1,4a,5,7-四氮雜-菲-10-甲醯胺；7-胺基-8-乙基-2-[4-(4-乙基哌嗪-1-基)-2-甲氧基苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(1-甲基哌啶-4-基甲氧基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺； 7-胺基-2-[4-(4-環丙基哌嗪-1-基)苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(4-乙基哌嗪-1-基)-2-甲基苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(4-乙基[1,4]二氮雜環庚烷-1-基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；8-(4-嗎啉-4-基苯基胺基)-5-酮基-1,2,3,5-四氫-3,7,9,9b-四氮雜-環戊幷(cyclopenta)[a]萘-4-甲醯胺；7-胺基-8-乙基-5-酮基-2-{4-[2-(3-三氟甲基哌啶-1-基)乙基]苯基胺基}-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(3-嗎啉-4-基丙基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-{4-[1-(2,2,2-三氟乙基)哌啶-4-基]苯基胺基}-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-(4-(S)-1-嗎啉-3-基甲基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-異丁基-2-[4-(2-嗎啉-4-基乙基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-{4-[2-(3-氟氮雜環丁烷-1-基)乙基]苯基胺基}-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[4-(2-嗎啉-4-基乙基)苯基胺基]-5-酮基-8-丙基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(2-羥基乙基)苯基胺基]-5-酮基- 5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-(4-羥乙基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-(2-甲基-1,2,3,4-四氫異喹啉-6-基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-{4-[2-(1,1-二酮基-1λ6-硫嗎啉-4-基)乙基]苯基胺基}-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-{4-[2-(4-甲基-3-酮基哌嗪-1-基)乙基]苯基胺基}-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-{4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-{4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(4-二甲基胺基甲基苯基胺基)-5-酮基-8-(2,2,2-三氟乙基)-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[3-氯-4-(4-吡咯啶-1-基哌啶-1-基)苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[3-氯-4-(4-吡咯啶-1-基哌啶-1-基)苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-(4-吡啶-2-基甲基苯基胺基)-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-{4-[2-(3,3-二氟吡咯啶-1-基)乙基]苯基胺基} -8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-(4-吡咯啶-3-基苯基胺基)-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-(4-吡咯啶-3-基苯基胺基)-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-[4-(2-哌啶-1-基乙基)苯基胺基]-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[4-(2-嗎啉-4-基乙基)苯基胺基]-5-酮基-8-(2,2,2-三氟乙基)-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-{4-[2-(4,4-二氟哌啶-1-基)乙基]苯基胺基}-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(1-甲基吡咯啶-3-基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-{4-[2-(3,3-二氟哌啶-1-基)乙基]苯基胺基}-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-(3-甲氧基-丙基)-2-[4-(2-嗎啉-4-基乙基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(1-甲基哌啶-3-基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(4-二甲基胺基甲基苯基胺基)-8-異丙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(4-二甲基胺基甲基苯基胺基)-8-異丙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-(4-哌啶-3-基苯基胺基)-5,8- 二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-(1,2,3,4-四氫異喹啉-7-基胺基)-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-(1,2,3,4-四氫異喹啉-7-基胺基)-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-(1,2,3,4-四氫異喹啉-6-基胺基)-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(1-甲基哌啶-4-基氧基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(2-嗎啉-4-基乙氧基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(3-二甲基胺基甲基苯基胺基)-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-[4-(4-吡咯啶-1-基哌啶-1-基)苯基胺基]-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-[4-(哌啶-4-基氧基)苯基胺基]-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-(3-胺基丙基)-2-(4-嗎啉-4-基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(2-嗎啉-4-基乙基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(4-二甲基胺基甲基苯基胺基)-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(1-乙基哌啶-4-基)苯基胺基]-5-酮 基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-(4-哌啶-4-基苯基胺基)-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[3-氯-4-(4-乙基哌嗪-1-基)苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[3-甲氧基-4-(3-哌啶-1-基丙氧基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-{4-[2-(4-三氟甲基哌啶-1-基)乙基]苯基胺基}-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-{4-[2-(順-2,6-二甲基嗎啉-4-基)乙基]苯基胺基}-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(4-二乙基胺基甲基苯基胺基)-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(4-二甲基胺基甲基苯基胺基)-8-(3-甲氧基-丙基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(4-乙基哌嗪-1-基)-2-氟苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-{4-[1-(2-氰基乙基)哌啶-4-基]苯基胺基}-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-{4-[1-(3-氟丙基)哌啶-4-基]苯基胺基}-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲酸醯胺；7-胺基-8-乙基-2-[4-(4-乙基哌嗪-1-基)-3-甲基苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺； 7-胺基-2-[4-(4-環丙基哌嗪-1-基)-2-乙基苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；(±)-7-胺基-2-反-[4-(2-二甲基胺基環丙基)苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[4-(4-環丙基哌嗪-1-基)-5-氟-2-甲氧基苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[4-(4-環丙基哌嗪-1-基)-3-氟-2-甲氧基苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[4-(4-環丙基哌嗪-1-基)-2-乙氧基苯基胺基]-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-(4-丙基苯基胺基)-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-(4-丙氧基苯基胺基)-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-(6-甲氧基吡啶-3-基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-(4-氟苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-(4-甲氧基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(苯并[1,3]二氧雜環戊烯(dioxol)-5-基胺基)-8-乙基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺； 7-胺基-8-乙基-5-酮基-2-(4-哌啶-1-基苯基胺基)-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；8-乙基-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-7-甲基胺基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-異丁基-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-環丙基甲基-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-(2-甲氧基乙基)-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-5-酮基-8-(四氫呋喃-2-基甲基)-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-{4-[1-(3,3,3-三氟丙基)氮雜環丁烷-3-基]苯基胺基}-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-{5-氟-2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-8-異丁基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-5-酮基-2-[4-(1,2,3,6-四氫吡啶-4-基)苯 基胺基]-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(2-甲氧基-4-哌啶-4-基苯基胺基)-5-酮基-8-苯基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-(2-羥基乙基)-2-(2-甲氧基-4-哌啶-4-基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-5-酮基-8-噻唑-2-基甲基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-5-酮基-8-噻唑-5-基甲基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-(2-羥基-2-甲基丙基)-2-(2-甲氧基-4-哌啶-4-基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；8-(2-乙醯基胺基乙基)-7-胺基-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-(2-胺基乙基)-2-(4-嗎啉-4-基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(4-嗎啉-4-基苯基胺基)-5-酮基-8-吡咯啶-3-基甲基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-[4-(4-乙基哌嗪-1-基)-2-羥基苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(4-嗎啉-4-基苯基胺基)-5-酮基-8-哌啶-4-基 甲基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(2-甲氧基-4-嗎啉-4-基苯基胺基)-5-酮基-8-吡咯啶-3-基甲基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-(2-甲氧基-4-哌啶-4-基苯基胺基)-4-甲基-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-5-酮基-8-噻吩-2-基甲基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-異丁基-2-[2-甲氧基-4-(4-嗎啉-4-基哌啶-1-基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-(4-嗎啉-4-基苯基胺基)-5-酮基-8-吡咯啶-2-基甲基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-乙基-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)-1,2,3,6-四氫吡啶-4-基]苯基胺基}-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[4-(4-乙基哌嗪-1-基)-2-甲氧基苯基胺基]-8-(2-羥基-2-甲基丙基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-(2-羥基-2-甲基丙基)-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-(2-羥基-2-甲基丙基)-2-[4-(4-乙基哌啶-1-基)-2-甲氧基苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶- 6-甲醯胺；7-胺基-2-[4-(1-環丙基哌啶-4-基)-2-甲氧基苯基胺基]-8-(2-羥基-2-甲基丙基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-(2-羥基-2-甲基丙基)-2-{2-甲氧基-4-[1-(2-甲氧基乙基)哌啶-4-基]苯基胺基}-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[2-甲氧基-4-(1-甲基哌啶-4-基)苯基胺基]-5-酮基-8-苯基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-(3-氟苯基)-2-[2-甲氧基-4-哌啶-4-基苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-(4-氟苯基)-2-[2-甲氧基-4-哌啶-4-基苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[2-甲氧基-4-哌啶-4-基苯基胺基]-5-酮基-8-間甲苯基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[2-甲氧基-4-哌啶-4-基苯基胺基]-5-酮基-8-對甲苯基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-(3-甲氧基苯基)-2-(2-甲氧基-4-哌啶-4-基苯基胺基)-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[2-甲氧基-4-(2-吡咯啶-1-基乙基)苯基胺基]-5-酮基-8-苯基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-8-(4-氟苯基)-2-[2-甲氧基-4-(1-甲基哌啶-4-基)苯基胺基]-5-酮基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺； 7-胺基-2-[2-甲氧基-4-(1-甲基哌啶-4-基)苯基胺基]-5-酮基-8-間甲苯基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-{2-甲氧基-4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯基胺基}-5-酮基-8-苯基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；7-胺基-2-[4-(4-乙基哌嗪-1-基)-2-甲氧基苯基胺基]-5-酮基-8-苯基-5,8-二氫吡啶并[2,3-d]嘧啶-6-甲醯胺；呈鹼或酸加成鹽形式。A compound according to claim 1 or 2, which is characterized in that it is selected from the group consisting of: 7-amino-8-ethyl-2-(4-hydroxyphenylamino)-5-one (oxo)-5,8 -dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-2-(benzothiazol-6-ylamino)-8-ethyl-5-one-5 , 8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-2-[4-(cyclopropanecarbonylmethylamino)phenylamino]-8-B 5--5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl-2-[4-(4-methyl Piperazine-1-carbonyl)phenylamino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-2-(4 -cyclopentyloxyphenylamino)-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8 -ethyl-2-[4-(4-ethylpiperazin-1-yl)phenylamino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6 -carbamamine; 7-amino-8-ethyl-5-keto-2-[4-(4-pyrrolidin-1-ylpiperidin-1-yl)phenylamino]-5,8 -dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl-5-keto-2-[4-(4-pyrrolidin-1-ylpiperidin Pyridin-1-yl)phenylamino]-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-ethyl-5-one Benzyl-2-[4-(4-pyrrolidin-1-ylpiperidin-1-yl)phenylamino]-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamidine Amine; 7-amino-8-cyclopentyl-2-(4-morpholin-4-ylphenylamino)-5-one-5,8-dihydropyrido[2,3-d] Pyrimidine-6-carbamide; 7-amino-8-ethyl-5-keto-2-[4-(piperidin-1-sulfonyl)phenylamino]-5,8-dihydro Pyrido[2,3-d]pyrimidin-6-carboxamide; 2-[4-(4-ethinylpiperazin-1-yl)phenylamino]-7-amino-8-ethyl -5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl-2-(4-morpholin-4-yl) Benzylamino)-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-ethyl-5-keto-2 -(quinolin-3-ylamino)-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-ethyl-5-keto- 2-[4-(3-piperidin-1-ylpropoxy)phenylamino]-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amine -8-ethyl-5-keto-2-(3,4,5,6-tetrahydro-2H-[1,2']bipyridin-5'-ylamino)-5,8-di Hydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl-5-keto-2-[4-(2-ketopyrrolidin-1-yl) Phenylamino]-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide 7-Amino-8-ethyl-5-keto-2-(quinolin-6-ylamino)-5,8-dihydropyrido[2,3-d]pyrimidin-6-formamidine Amine; 7-amino-8-ethyl-2-(3-morpholin-4-ylphenylamino)-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine -6-carbamamine; 7-amino-2-(2,3-dihydrobenzo[1,4]dioxine-6-ylamino)-8-ethyl- 5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl-2-(3-fluoro-4-hydroxyphenyl) Amino)-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl-2-(3-methylsulfide Phenylamino)-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-ethyl-2-(4- Morpholin-4-ylphenylamino)-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl- 2-(4-morpholin-4-ylphenylamino)-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino group- 8-ethyl-2-(4-morpholin-4-ylphenylamino)-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-Amino-8-ethyl-2-(2-fluorophenylamino)-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-Amino-2-[4-(4,4-difluoro[1,4'] Pyridin-1'-yl)-2-methoxyphenylamino]-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamidine Amine; 7-amino-8-ethyl-2-[2-methoxy-4-(4-trifluoromethyl[1,4']bipiperidin-1'-yl)phenylamino] 5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-2-{4-[4-(3,3-difluoropyrrolidine) -1-yl)piperidin-1-yl]-2-methoxyphenylamino}-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine -6-carbamamine; 7-amino-8-ethyl-2-[4-(4-ethylpiperazin-1-yl)-2-fluoro-6-methoxyphenylamino]- 5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-2-[4-(1-cyclopropylpiperidin-4-yl) -2-methoxyphenylamino]-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino group -2-(2-dimethylaminomethyl) Alkan-6-ylamino)-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-2-[ 5-chloro-4-(4-cyclopropylpiperazin-1-yl)-2-methoxyphenylamino]-8-ethyl-5-keto-5,8-dihydropyridin[ 2,3-d]pyrimidine-6-formamide; 7-amino-8-ethyl-2-[2-methoxy-4-(4-morpholin-4-ylpiperidin-1-yl) Phenylamino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-2-[4-(4-cyclopropane) Piperazin-1-yl)-2-difluoromethoxyphenylamino]-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6 -carbamamine; 7-amino-2-[4-(4-cyclopropylpiperazin-1-yl)-2-methoxyphenylamino]-8-ethyl-5-one- 5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-ethyl-2-{2-methoxy-4-[1-(3, 3,3-trifluoropropyl)piperidin-4-yl]phenylamino}-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-Amino-2-[2-chloro-4-(4-ethylpiperazin-1-yl)phenylamino]-8-ethyl-5-keto-5,8-dihydropyridine [2,3-d]pyrimidine-6-formamide; 7-amino-8-ethyl-2-[4-(4-ethylpiperazin-1-yl)-3-trifluoromethylbenzene Amino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6- Indoleamine; 7-amino-8-ethyl-2-(4-morpholin-4-ylmethylphenylamino)-5-keto-5,8-dihydropyrido[2,3- d]pyrimidine-6-carbamide; 7-amino-8-ethyl-5-keto-2-{4-[4-(3,3,3-trifluoropropyl)piperazine-1- Phenylamino}-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-ethyl-2-[4-(4-ethyl Piperazin-1-yl)-3-fluorophenylamino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 6-(4 -morpholin-4-ylphenylamino)-9-keto-1,3,4,9-tetrahydro-2H-1,4a,5,7-tetraaza-phenanthrene-10-carboxamide 7-Amino-8-ethyl-2-[4-(4-ethylpiperazin-1-yl)-2-methoxyphenylamino]-5-one-5,8-di Hydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl-2-[4-(1-methylpiperidin-4-ylmethoxy)phenyl Amino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-2-[4-(4-cyclopropylpiperazine) -1-yl)phenylamino]-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8 -ethyl-2-[4-(4-ethylpiperazin-1-yl)-2-methylphenylamino]-5-keto-5,8-dihydropyrido[2,3- d]pyrimidine-6-formamide; 7-amino-8-ethyl-2-[4-(4-ethyl[1,4] Azepan-1-yl)phenylamino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 8-(4-? Phenyl-4-ylphenylamino)-5-keto-1,2,3,5-tetrahydro-3,7,9,9b-tetraaza-cyclopenta[cyclo][na]-naphthalene- 4-carbamide; 7-amino-8-ethyl-5-keto-2-{4-[2-(3-trifluoromethylpiperidin-1-yl)ethyl]phenylamino }-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-ethyl-2-[4-(3-morpholin-4-ylpropane) Phenylamino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-ethyl-5-one -2-{4-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]phenylamino}-5,8-dihydropyrido[2,3-d]pyrimidine -6-carbamamine; 7-amino-8-ethyl-2-(4-(S)-1-morpholin-3-ylmethylphenylamino)-5-keto-5,8 -dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-isobutyl-2-[4-(2-morpholin-4-ylethyl)phenyl Amino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-ethyl-2-{4-[2- (3-Fluoroazetidin-1-yl)ethyl]phenylamino}-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide ;7-Amino-2-[4-(2-morpholin-4-ylethyl)phenylamino]- 5-keto-8-propyl-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl-2-[4-(2 -hydroxyethyl)phenylamino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-ethyl-2 -(4-hydroxyethylphenylamino)-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl -2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-ylamino)-5-keto-5,8-dihydropyrido[2,3-d] Pyrimidine-6-formamide; 7-amino-2-{4-[2-(1,1-dione-1λ6-thiomorpholin-4-yl)ethyl]phenylamino}-8 -ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-ethyl-2-{4-[2- (4-methyl-3-ketopiperazin-1-yl)ethyl]phenylamino}-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6- Methionamine; 7-amino-8-ethyl-5-keto-2-{4-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]phenylamino }-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-ethyl-5-keto-2-{4-[1-(3 ,3,3-trifluoropropyl)piperidin-4-yl]phenylamino}-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino group -2-(4-dimethylaminomethylphenylamino)-5-keto-8-(2,2,2- Fluoroethyl)-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-2-[3-chloro-4-(4-pyrrolidine-1- Isopiperidin-1-yl)phenylamino]-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amine Benzyl-2-[3-chloro-4-(4-pyrrolidin-1-ylpiperidin-1-yl)phenylamino]-8-ethyl-5-keto-5,8-dihydropyridine And [2,3-d]pyrimidine-6-formamide; 7-amino-8-ethyl-5-keto-2-(4-pyridin-2-ylmethylphenylamino)-5 , 8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-2-{4-[2-(3,3-difluoropyrrolidin-1-yl) Phenylamino}-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-ethyl -5-keto-2-(4-pyrrolidin-3-ylphenylamino)-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino group -8-ethyl-5-keto-2-(4-pyrrolidin-3-ylphenylamino)-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide 7-Amino-8-ethyl-5-keto-2-[4-(2-piperidin-1-ylethyl)phenylamino]-5,8-dihydropyrido[2, 3-d]pyrimidin-6-formamide; 7-amino-2-[4-(2-morpholin-4-ylethyl)phenylamino]-5-keto-8-(2, 2,2-trifluoroethyl)-5,8-dihydropyrido[2,3-d] Pyrimidine-6-carbamide; 7-amino-2-{4-[2-(4,4-difluoropiperidin-1-yl)ethyl]phenylamino}-8-ethyl-5 -keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl-2-[4-(1-methylpyrrolidine- 3-yl)phenylamino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-2-{4-[2 -(3,3-difluoropiperidin-1-yl)ethyl]phenylamino}-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine -6-carbamamine; 7-amino-8-(3-methoxy-propyl)-2-[4-(2-morpholin-4-ylethyl)phenylamino]-5- Keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-ethyl-2-[4-(1-methylpiperidine-3 -yl)phenylamino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-2-(4-dimethyl Aminomethylphenylamino)-8-isopropyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-2 -(4-dimethylaminomethylphenylamino)-8-isopropyl-5-one-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide 7-Amino-8-ethyl-5-keto-2-(4-piperidin-3-ylphenylamino)-5,8-dihydropyrido[2,3-d]pyrimidine- 6-carbamide; 7-amino-8-ethyl-5-one 2-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; -amino-8-ethyl-5-keto-2-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)-5,8-dihydropyrido[2,3 -d]pyrimidine-6-carbamide; 7-amino-8-ethyl-5-keto-2-(1,2,3,4-tetrahydroisoquinolin-6-ylamino)- 5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-ethyl-2-[4-(1-methylpiperidin-4-yloxy) Phenylamino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl-2-[4 -(2-morpholin-4-ylethoxy)phenylamino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7- Amino-2-(3-dimethylaminomethylphenylamino)-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6- Methionamine; 7-amino-8-ethyl-5-keto-2-[4-(4-pyrrolidin-1-ylpiperidin-1-yl)phenylamino]-5,8- Dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl-5-keto-2-[4-(piperidin-4-yloxy)benzene Amino]-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-(3-aminopropyl)-2-(4-? Polin-4-ylphenylamino)-5-keto-5,8-dihydropyrido[2,3 -d]pyrimidine-6-carbamide; 7-amino-8-ethyl-2-[4-(2-morpholin-4-ylethyl)phenylamino]-5-keto-5 , 8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-2-(4-dimethylaminomethylphenylamino)-8-ethyl- 5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl-2-[4-(1-ethylpiperidine) 4-yl)phenylamino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-ethyl-5 -keto-2-(4-piperidin-4-ylphenylamino)-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-2 -[3-chloro-4-(4-ethylpiperazin-1-yl)phenylamino]-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d Pyrimidine-6-formamide; 7-amino-8-ethyl-2-[3-methoxy-4-(3-piperidin-1-ylpropoxy)phenylamino]-5 -keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-ethyl-5-keto-2-{4-[2- (4-Trifluoromethylpiperidin-1-yl)ethyl]phenylamino}-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino group -2-{4-[2-(cis-2,6-dimethylmorpholin-4-yl)ethyl]phenylamino}-8-ethyl-5-keto-5,8-di Hydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-2- (4-diethylaminomethylphenylamino)-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; -amino-2-(4-dimethylaminomethylphenylamino)-8-(3-methoxy-propyl)-5-one-5-8-dihydropyrido[2] , 3-d] pyrimidine-6-formamide; 7-amino-8-ethyl-2-[4-(4-ethylpiperazin-1-yl)-2-fluorophenylamino]- 5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-2-{4-[1-(2-cyanoethyl)per Pyridin-4-yl]phenylamino}-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino group- 8-ethyl-2-{4-[1-(3-fluoropropyl)piperidin-4-yl]phenylamino}-5-keto-5,8-dihydropyrido[2,3 -d]pyrimidine-6-formic acid decylamine; 7-amino-8-ethyl-2-[4-(4-ethylpiperazin-1-yl)-3-methylphenylamino]-5 -keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-2-[4-(4-cyclopropylpiperazin-1-yl) -2-ethylphenylamino]-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; (±)-7- Amino-2-trans-[4-(2-dimethylaminocyclopropyl)phenylamino]-8-ethyl-5-keto-5,8-dihydropyrido[2,3 -d]pyrimidine-6-carbamide; 7-amino-2-[4-(4 -cyclopropylpiperazin-1-yl)-5-fluoro-2-methoxyphenylamino]-8-ethyl-5-keto-5,8-dihydropyrido[2,3- d]pyrimidine-6-formamide; 7-amino-2-[4-(4-cyclopropylpiperazin-1-yl)-3-fluoro-2-methoxyphenylamino]-8 -ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-2-[4-(4-cyclopropylpiperazine) -1-yl)-2-ethoxyphenylamino]-8-ethyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-Amino-8-ethyl-5-keto-2-(4-propylphenylamino)-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide 7-Amino-8-ethyl-5-keto-2-(4-propoxyphenylamino)-5,8-dihydropyrido[2,3-d]pyrimidine-6- Indoleamine; 7-amino-8-ethyl-2-(6-methoxypyridin-3-ylamino)-5-keto-5,8-dihydropyrido[2,3-d] Pyrimidine-6-formamide; 7-amino-8-ethyl-2-(4-fluorophenylamino)-5-keto-5,8-dihydropyrido[2,3-d] Pyrimidine-6-formamide; 7-amino-8-ethyl-2-(4-methoxyphenylamino)-5-keto-5,8-dihydropyrido[2,3- d]pyrimidine-6-formamide; 7-amino-2-(benzo[1,3]dioxol-5-ylamino)-8-ethyl-5-one Radyl-5,8-dihydropyrido[2,3-d] Pyrimidine-6-formamide; 7-amino-8-ethyl-5-keto-2-(4-piperidin-1-ylphenylamino)-5,8-dihydropyrido[2 , 3-d] pyrimidine-6-formamide; 8-ethyl-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperidin-4-yl Phenylamino}-7-methylamino-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-iso Butyl-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]phenylamino}-5-one-5,8 -dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-cyclopropylmethyl-2-{2-methoxy-4-[1-(3, 3,3-trifluoropropyl)piperidin-4-yl]phenylamino}-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-Amino-8-(2-methoxyethyl)-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperidin-4-yl] Phenylamino}-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-2-{2-methoxy-4- [1-(3,3,3-Trifluoropropyl)piperidin-4-yl]phenylamino}-5-keto-8-(tetrahydrofuran-2-ylmethyl)-5,8-di Hydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-ethyl-5-keto-2-{4-[1-(3,3,3-trifluoro) Propyl)azetidin-3-yl]phenylamino}-5,8-dihydropyrido[2,3-d] Pyrimidine-6-carbamide; 7-amino-2-{5-fluoro-2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperidin-4-yl] Phenylamino}-8-isobutyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-ethyl- 5-keto-2-[4-(1,2,3,6-tetrahydropyridin-4-yl)phenylamino]-5,8-dihydropyrido[2,3-d]pyrimidine- 6-carbamide; 7-amino-2-(2-methoxy-4-piperidin-4-ylphenylamino)-5-keto-8-phenyl-5,8-dihydro Pyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-(2-hydroxyethyl)-2-(2-methoxy-4-piperidin-4-ylbenzene Amino)-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-2-{2-methoxy-4-[ 1-(3,3,3-trifluoropropyl)piperidin-4-yl]phenylamino}-5-keto-8-thiazol-2-ylmethyl-5,8-dihydropyridine [2,3-d]pyrimidine-6-carbamide; 7-amino-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperidine-4 -yl]phenylamino}-5-keto-8-thiazol-5-ylmethyl-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amine -8-(2-hydroxy-2-methylpropyl)-2-(2-methoxy-4-piperidin-4-ylphenylamino)-5-one-5,8-di Hydropyrido[2,3-d]pyrimidin-6-carboxamide; 8-(2-ethenylamino) -7-Amino-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]phenylamino}-5-one 5-,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-(2-aminoethyl)-2-(4-morpholine-4 -phenylphenylamino)-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-2-(4-morpholin-4 -phenylphenylamino)-5-keto-8-pyrrolidin-3-ylmethyl-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amine -8-ethyl-2-[4-(4-ethylpiperazin-1-yl)-2-hydroxyphenylamino]-5-keto-5,8-dihydropyrido[2, 3-d]pyrimidine-6-carbamide; 7-amino-2-(4-morpholin-4-ylphenylamino)-5-one-8-piperidin-4-ylmethyl- 5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-2-(2-methoxy-4-morpholin-4-ylphenylamino) -5-keto-8-pyrrolidin-3-ylmethyl-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-ethyl- 2-(2-Methoxy-4-piperidin-4-ylphenylamino)-4-methyl-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine- 6-carbamide; 7-amino-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]phenylamino}- 5-keto-8-thiophen-2-ylmethyl-5,8-dihydropyrido[2, 3-d]pyrimidine-6-carbamide; 7-amino-8-isobutyl-2-[2-methoxy-4-(4-morpholin-4-ylpiperidin-1-yl) Phenylamino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-2-(4-morpholin-4-yl) Phenylamino)-5-keto-8-pyrrolidin-2-ylmethyl-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino group- 8-ethyl-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl Amino}-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-2-[4-(4-ethylpiperazine- 1-yl)-2-methoxyphenylamino]-8-(2-hydroxy-2-methylpropyl)-5-one-5,8-dihydropyrido[2,3-d Pyrimidine-6-formamide; 7-amino-8-(2-hydroxy-2-methylpropyl)-2-{2-methoxy-4-[1-(3,3,3- Trifluoropropyl)piperidin-4-yl]phenylamino}-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino group 8-(2-hydroxy-2-methylpropyl)-2-[4-(4-ethylpiperidin-1-yl)-2-methoxyphenylamino]-5-one- 5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-2-[4-(1-cyclopropylpiperidin-4-yl)-2-methyl Oxyphenylamino]-8-(2-hydroxy-2-methylpropyl)-5-one-5,8-di Pyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-(2-hydroxy-2-methylpropyl)-2-{2-methoxy-4-[1 -(2-methoxyethyl)piperidin-4-yl]phenylamino}-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide 7-Amino-2-[2-methoxy-4-(1-methylpiperidin-4-yl)phenylamino]-5-keto-8-phenyl-5,8-di Hydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-(3-fluorophenyl)-2-[2-methoxy-4-piperidin-4-yl Phenylamino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-(4-fluorophenyl)-2 -[2-methoxy-4-piperidin-4-ylphenylamino]-5-keto-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-Amino-2-[2-methoxy-4-piperidin-4-ylphenylamino]-5-keto-8-m-tolyl-5,8-dihydropyrido[2, 3-d]pyrimidine-6-carbamide; 7-amino-2-[2-methoxy-4-piperidin-4-ylphenylamino]-5-one-8-p-tolyl -5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-8-(3-methoxyphenyl)-2-(2-methoxy- 4-piperidin-4-ylphenylamino)-5-keto-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide; 7-amino-2-[ 2-methoxy-4-(2-pyrrolidin-1-ylethyl) Phenylamino]-5-keto-8-phenyl-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-8-(4-fluoro Phenyl)-2-[2-methoxy-4-(1-methylpiperidin-4-yl)phenylamino]-5-keto-5,8-dihydropyrido[2,3 -d]pyrimidine-6-carbamide; 7-amino-2-[2-methoxy-4-(1-methylpiperidin-4-yl)phenylamino]-5-one- 8-m-tolyl-5,8-dihydropyrido[2,3-d]pyrimidin-6-carboxamide; 7-amino-2-{2-methoxy-4-[1-(3 ,3,3-trifluoropropyl)piperidin-4-yl]phenylamino}-5-keto-8-phenyl-5,8-dihydropyrido[2,3-d]pyrimidine- 6-carbamide; 7-amino-2-[4-(4-ethylpiperazin-1-yl)-2-methoxyphenylamino]-5-keto-8-phenyl- 5,8-Dihydropyrido[2,3-d]pyrimidin-6-carboxamide; in the form of a base or acid addition salt. 一種製備如請求項1至10中任一項之式(I)化合物的方法，其特徵在於包含使式(IX)之化合物 與式(A)之一級胺反應 其中R1 、R2 、R3 、R4 及R5 如請求項1至9中任一項所定義且t 表示1或2。A process for the preparation of a compound of formula (I) according to any one of claims 1 to 10, characterized in that it comprises a compound of formula (IX) Reaction with one of the amines of formula (A) Wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined in any one of claims 1 to 9 and t represents 1 or 2. 一種製備如請求項1至10中任一項之式(I)化合物的方法，其特徵在於包含使通式(XIV)或(XV)之化合物 與通式(A)之化合物反應 其中R1 、R2 、R3 、R4 、R5 及R6 如請求項1至9中任一項所定義。A process for the preparation of a compound of the formula (I) according to any one of claims 1 to 10, characterized in that it comprises a compound of the formula (XIV) or (XV) Reacting with a compound of the formula (A) Wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in any one of claims 1 to 9. 一種式(VII)之化合物， a compound of formula (VII), 一種式(VIII)之化合物， 其中R5 如請求項1、5及6中任一項所定義。a compound of formula (VIII), Wherein R 5 is as defined in any one of claims 1, 5 and 6. 一種式(IX)之化合物， 其中R 5 如請求項1、5及6中任一項所定義，且t 表示1或2。a compound of formula (IX), Wherein R 5 is as defined in any one of claims 1, 5 and 6, and t represents 1 or 2. 一種式(XV)之化合物， 其中R 5 及R 6 如請求項1、5及6中任一項所定義。a compound of formula (XV), Wherein R 5 and R 6 are as defined in any one of claims 1, 5 and 6. 一種藥劑，其特徵在於包含如請求項1至10中任一項之式(I)化合物或該化合物與醫藥學上可接受酸之加成鹽。 An agent comprising a compound of formula (I) according to any one of claims 1 to 10 or an addition salt of the compound with a pharmaceutically acceptable acid. 一種醫藥組合物，其特徵在於包含如請求項1至10中任一項之式(I)化合物或該化合物之醫藥學上可接受之鹽，以及至少一種醫藥學上可接受之賦形劑。 A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt of the compound, and at least one pharmaceutically acceptable excipient. 如請求項1或2之式(I)化合物，其係用於治療涉及激酶Ca2+ /鈣調蛋白依賴性蛋白激酶II之任何病變。A compound of formula (I) according to claim 1 or 2 for use in the treatment of any pathology involving kinase Ca 2+ /calmodulin-dependent protein kinase II. 如請求項19之化合物，其係用於治療心血管病變，以及與內皮功能障礙相關之血管病變，以及與纖維化相關的病變，以及急性病變，以及與神經元死亡或變性相關的病變，以及發炎來源之病變。 The compound of claim 19, for use in the treatment of cardiovascular disorders, and vascular lesions associated with endothelial dysfunction, and fibrosis-related lesions, as well as acute lesions, and lesions associated with neuronal death or degeneration, and Inflamed source of lesions. 如請求項20之化合物，其中該心血管病變包括心肌梗 塞，心室肥大，心肌纖維化，心機能不全，心律不整及再狹窄。 The compound of claim 20, wherein the cardiovascular disease comprises a myocardial infarction Plug, ventricular hypertrophy, myocardial fibrosis, cardiac insufficiency, arrhythmia and restenosis. 如請求項20之化合物，其中該與內皮功能障礙相關之血管病變包括動脈粥樣硬化。 The compound of claim 20, wherein the vascular lesion associated with endothelial dysfunction comprises atherosclerosis. 如請求項20之化合物，其中該與纖維化相關的病變包括肝纖維化，胰纖維化，腎纖維化，肺纖維化，皮膚纖維化，腸纖維化及眼纖維化之發展，腎臟移植及肝臟移植。 The compound of claim 20, wherein the fibrosis-related lesions include liver fibrosis, pancreatic fibrosis, renal fibrosis, pulmonary fibrosis, skin fibrosis, intestinal fibrosis, and development of ocular fibrosis, kidney transplantation and liver transplant. 如請求項20之化合物，其中該急性病變包括急性腎功能不全，急性肺功能不全及急性肝功能不全。 The compound of claim 20, wherein the acute condition comprises acute renal insufficiency, acute pulmonary insufficiency, and acute hepatic insufficiency. 如請求項20之化合物，其中該與神經元死亡或變性相關的病變包括中風及帕金森氏症(Parkinson's disease)。 The compound of claim 20, wherein the lesion associated with neuronal death or degeneration comprises stroke and Parkinson's disease. 如請求項20之化合物，其中該發炎來源之病變係慢性疼痛或類風濕性關節炎。 The compound of claim 20, wherein the inflammatory source is chronic pain or rheumatoid arthritis.
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